部份中文霉酚酸酯处方资料（仅供参考） 英文药名: Cellcept(Mycophenolate Mofetil Powder for Infusion) 中文药名: 骁悉（霉酚酸酯输液） 生产厂家: Roche Pharmaceuticals 中文药名: 骁悉（霉酚酸酯） 规格： 霉酚酸酯胶囊 250mg 霉酚酸酯片 500mg 霉酚酸酯注射液 500mg/Vial 霉酚酸酯悬浮液 200mg/ml 药理作用 霉酚酸酯(简称MMF)是霉酚酸(MPA)的2-乙基酯类衍生物。MPA是高效、选择性、非竞争性、可逆性的次黄嘌呤单核苷酸脱氢酶(IMPDH)抑制剂，可抑制鸟嘌呤核苷酸的经典合成途径。MPA对淋巴细胞具有高度选择作用。 药代动力学 口服后迅速大量吸收，并代谢为活性成份MPA。口服平均生物利用度为静脉注射的94%(根据MPA曲线下面积)，口服后在循环中测不出MMF。 肾移植病人口服MMF，其吸收不受食物影响，但进食后血MPA峰值将降低40%。由于肠肝循环作用，服药后6-12小时将出现第二个血浆 MPA高峰，与消胆胺同时服用将使MPA曲线下面积减少约40%，表明MPA通过肠肝循环的量很多。在临床有效浓度下，97%的MPA与血浆蛋白结合。 MPA主要通过葡萄糖醛酸转移酶，代谢成MPA的的酚化葡萄糖苷糖(MPAG)，MPAG无药理活性。MMF代谢成的MPA有极少量(<1%)从尿液排出，多数(87%)以MPAG的形式从尿液排出。 移植后近期内(<40日)，平均曲线下面积(AUG)和血峰值(Cmax)比正常志愿者和移植肾功能稳定的病人约低50%。单剂研究显示，严重的慢性肾功能损害(肾小球滤过率<25 mL/分/1.73 m2)。MPA曲线下面积比正常志愿者和轻度肾功能损害病人高25-75%。同样情况下，MPAG曲线下面积高3-6倍，与MPAG主要由肾脏排出一致。尚未进行严重慢性肾功能损害病人的MMF多次剂量药物动力学研究。 移植手术后，肾功能延迟恢复的MPA 0-12小时曲线下面积与无肾功能延迟恢复的者无显著差异。但无活性成分的MPAG，其0-12小时曲线下面积比肾功能正常恢复病人高2-3倍。在酒精性肝硬化志愿者，肝脏实质疾病对MPA的糖苷酸化过程相对无影响，严重的胆道损害，如原发性胆性肝硬化，可能对这一过程产生影响。 适应症 预防同种肾移植病人的排斥反应及治疗难治性排斥反应，可与环孢素和肾上腺皮质激素同时应用。 用法用量 预防排斥剂量: 应于移植72小时内开始服用。肾移植病人服用推荐剂量为1g，1日2次。口服2g/日比口服3g/日安全性更高。 治疗难治性排斥反应: 在临床试验中，治疗难治性排斥的推荐剂量为1.5g/次，2次/日。如果发生中性粒细胞减少(中性粒细胞计数绝对值小于1.3 x103/mL)，应停药或减量。对有严重慢性肾功能损害的病人(肾小球滤过率小于25mL/分/1.73 m2)，应避免超过1g/次，每日2次的剂量(移植后即刻使用除外)。对这些病人应仔细观察。对移植后肾功能延期恢复的病人不需要作剂量调整。 任何疑问,请遵医嘱! 不良反应 服用本药后，主要的不良反应包括：呕吐、腹泻等胃肠道症状，白细胞减少症，败血症，尿频以及某些类型的感染的发生率增加。偶见血尿酸升高、高血钾、肌痛或嗜睡。 禁忌症 对MMF或MPA发生过敏反应的病人不能使用本药。 注意事项 服用本药的病人在第一个月每周1次进行全血细胞计数，第二和第三个月每月2次，余下的一年中每月1次，如果发生中性粒细胞减少(中性粒细胞绝对计数小于1.3x103/uL)时，应停止或减量使用本药，并对这些病人密切观察。 严重慢性肾功能损害(肾小球滤过率小于25mL/分/1.73 m2)的病人服用单剂量后，血浆MPA和MPAG的曲线下面积比轻度肾功能损害的病人及健康人高。应避免使用超过1g/次，每日2次的剂量，并且应对这些病人密切观察。肾移植后肾功能恢复的病人，平均0-12小时 MPA曲线下面积与正常恢复病人相仿。但MPAG的0-12小时曲线下面积前者比后者高2-3倍。对这些肾功能延迟恢复的病人无须作剂量调整，但应密切观察。 接受免疫抑制疗法的病人常使用联合用药方式。本药作为联合应用免疫抑制药物时，有增加淋巴瘤和其它恶性肿瘤(特别是皮肤瘤)发生的危险。这一危险性和免疫抑制的强度和持续时间有关，孕妇及哺乳期妇妇用药中应为是否可从人乳中分泌尚不清楚。免疫系统的过度抑制也可能导致对感染的易感性增加。 临床试验中，本药已与以下药物联合应用：抗淋巴细胞球抗体、环孢素和皮质激素类药物，以预防排斥反应和治疗难治性排斥反应。 孕妇及哺乳期妇女用药 动物实验中发现本药有致胎儿畸形的可能。尽管还未对孕妇作充分和良好的对照研究，只有在本药的潜在优点超过对胎儿的潜在危险时方予应用。应在妊娠试验阴性后，才开始服用本药。服用本药期间，应采取有效避孕措施。对大鼠的研究发现MMF可通过乳汁分泌，是否可从人乳中分泌骁尚不清楚，并且，MMF能对哺乳期婴儿可能有潜在的严重副作用，应根据MMF对于母亲的重要性作出用药决定。 儿童用药 儿童使用该药的安全性和有效性尚未确证。 药物相互作用 不能与硫唑嘌呤同时使用，对这两种药物的同时使用尚未进行试验。 已注意到消胆胺能显著减少MPA线曲下面积。 本药不应与能干扰肠肝再循环的药物同时使用，因这些药物可能会降低本药的药效。和阿昔洛韦同时服用时，MPAG和阿昔洛韦 的血浆浓度较两种药物单独服用时为高。当肾功损害时，MPAG和阿昔洛韦的血浆浓度都升高。这两种药物竞争性地通过肾小管排出，可能会进一步增加两种药物的浓度。 制酸药物和氢氧化镁以及氢氧化铝：同时服用制酸剂时，MMF的吸收减少。 消胆胺： 健康人先期服用消胆胺4 g/次，每日3次，4日后给予单剂量MMF 1.5 g，MPA的曲线下面积减少40%。 环孢素A的药物动力学不受MMF的影响。 更昔洛韦： 未观察到MMF和静脉注射更昔洛韦之间有药物动力学的交叉作用。 口服避孕药： 目前尚未发现MMF和口服避孕药1 mg炔诺酮/35 ug炔雌醇之间有相互影响。但这只是单次剂量研究所得出的结论，并不能排除长期服用本药后改变口服避孕药的药物动力学的可能性。这可能导致口服避孕药的药效降低。 磺胺甲基异唑：对MPA的生物利用度无影响。 其它药物： 给猴子同时服用丙磺舒和MMF，可使血浆MPAG曲线下面积增加3倍。为此，其它经肾小管排出的药物可与MPAG竞争，从而使血浆MPAG或这些药物的浓度升高。 药物过量 在人类尚无MMF剂量过大的报道。血透不能清除MPA，而当MPA 血浆浓度极高时(>100 ug/mL)，能清除小部分MPAG。MPA可通过药物排出增加(如给予消胆胺)而得到清除。 Cellcept 500mg powder for concentrate for solution for infusion 1. Name of the medicinal product CellCept 500 mg powder for concentrate for solution for infusion. 2. Qualitative and quantitative composition Each vial contains the equivalent of 500 mg mycophenolate mofetil (as hydrochloride salt). For the full list of excipients, see section 6.1. 3. Pharmaceutical form Powder for concentrate for solution for infusion. CellCept 500 mg powder for concentrate for solution for infusion must be reconstituted and further diluted with glucose intravenous infusion 5% prior to administration to the patient (see section 6.6). 4. Clinical particulars 4.1 Therapeutic indications CellCept 500 mg powder for concentrate for solution for infusion is indicated in combination with ciclosporin and corticosteroids for the prophylaxis of acute transplant rejection in patients receiving allogeneic renal or hepatic transplants. 4.2 Posology and method of administration Treatment with CellCept should be initiated and maintained by appropriately qualified transplant specialists. CAUTION: CELLCEPT I.V. SOLUTION MUST NOT BE ADMINISTERED BY RAPID OR BOLUS INTRAVENOUS INJECTION. Posology CellCept 500 mg powder for concentrate for solution for infusion is an alternative dosage form to CellCept oral forms (capsules, tablets and powder for oral suspension) that may be administered for up to 14 days. The initial dose of CellCept 500 mg powder for concentrate for solution for infusion should be given within 24 hours following transplantation. Renal transplant The recommended dose in renal transplant patients is 1 g administered twice daily (2 g daily dose). Hepatic transplant The recommended dose of CellCept for infusion in hepatic transplant patients is 1 g administered twice daily (2 g daily dose). IV CellCept should continue for the first 4 days following hepatic transplant, with oral CellCept initiated as soon after this as it can be tolerated. The recommended dose of oral CellCept in hepatic transplant patients is 1.5 g administered twice daily (3 g daily dose). Use in special populations Paediatric population Safety and efficacy of CellCept for infusion in paediatric patients have not been established. No pharmacokinetic data with CellCept for infusion are available for paediatric renal transplant patients. No pharmacokinetic data are available for paediatric patients following hepatic transplants. Elderly The recommended dose of 1 g administered twice a day for renal or hepatic transplant patients is appropriate for the elderly. Renal impairment In renal transplant patients with severe chronic renal impairment (glomerular filtration rate < 25 mL/min/1.73 m2), outside the immediate post-transplant period, doses greater than 1 g administered twice a day should be avoided. These patients should also be carefully observed. No dose adjustments are needed in patients experiencing delayed renal graft function post-operatively (see section 5.2). No data are available for hepatic transplant patients with severe chronic renal impairment. Severe hepatic impairment No dose adjustments are needed for renal transplant patients with severe hepatic parenchymal disease. Treatment during rejection episodes Mycophenolic acid (MPA) is the active metabolite of mycophenolate mofetil. Renal transplant rejection does not lead to changes in MPA pharmacokinetics; dosage reduction or interruption of CellCept is not required. No pharmacokinetic data are available during hepatic transplant rejection. Method of administration Following reconstitution to a concentration of 6 mg/mL, CellCept 500 mg powder for concentrate for solution for infusion must be administered by slow intravenous infusion over a period of 2 hours by either a peripheral or a central vein (see section 6.6). Precautions to be taken before handling or administering the medicinal product Because mycophenolate mofetil has demonstrated teratogenic effects in rats and rabbits, avoid direct contact of the dry powder or prepared solutions of CellCept 500 mg powder for concentrate for solution for infusion with skin or mucous membranes. If such contact occurs, wash thoroughly with soap and water; rinse eyes with plain water. For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6. 4.3 Contraindications • CellCept should not be given to patients with hypersensitivity to mycophenolate mofetil, mycophenolic acid or to any of the excipients listed in section 6.1. Hypersensitivity reactions to CellCept have been observed (see section 4.8). CellCept 500 mg powder for concentrate for solution for infusion is contraindicated in patients who are allergic to polysorbate 80. • CellCept should not be given to women of childbearing potential who are not using highly effective contraception (see section 4.6). • CellCept treatment should not be initiated in women of child bearing potential without providing a pregnancy test result to rule out unintended use in pregnancy (see section 4.6). • CellCept should not to be used in pregnancy unless there is no suitable alternative treatment to prevent transplant rejection (see section 4.6). • CellCept should not be given to women who are breastfeeding (see section 4.6). 4.4 Special warnings and precautions for use Neoplasms Patients receiving immunosuppressive regimens involving combinations of medicinal products, including CellCept, are at increased risk of developing lymphomas and other malignancies, particularly of the skin (see section 4.8). The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. As general advice to minimise the risk for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor. Infections Patients treated with immunosuppressants, including CellCept, are at increased risk for opportunistic infections (bacterial, fungal, viral and protozoal), fatal infections and sepsis (see section 4.8). Such infections include latent viral reactivation, such as hepatitis B or hepatitis C reactivation and infections caused by polyomaviruses (BK virus associated nephropathy, JC virus associated progressive multifocal leukoencephalopathy PML). Cases of hepatitis due to reactivation of hepatitis B or hepatitis C have been reported in carrier patients treated with immunosuppressants. These infections are often related to a high total immunosuppressive burden and may lead to serious or fatal conditions that physicians should consider in the differential diagnosis in immunosuppressed patients with deteriorating renal function or neurological symptoms. There have been reports of hypogammaglobulinaemia in association with recurrent infections in patients receiving CellCept in combination with other immunosuppressants. In some of these cases switching CellCept to an alternative immunosuppressant resulted in serum IgG levels returning to normal. Patients on CellCept who develop recurrent infections should have their serum immunoglobulins measured. In cases of sustained, clinically relevant hypogammaglobulinaemia, appropriate clinical action should be considered taking into account the potent cytostatic effects that mycophenolic acid has on T- and B-lymphocytes. There have been published reports of bronchiectasis in adults and children who received CellCept in combination with other immunosuppressants. In some of these cases switching CellCept to another immunosuppressant resulted in improvement in respiratory symptoms. The risk of bronchiectasis may be linked to hypogammaglobulinaemia or to a direct effect on the lung. There have also been isolated reports of interstitial lung disease and pulmonary fibrosis, some of which were fatal (see section 4.8). It is recommended that patients who develop persistent pulmonary symptoms, such as cough and dyspnoea, are investigated. Blood and immune system Patients receiving CellCept should be monitored for neutropenia, which may be related to CellCept itself, concomitant medications, viral infections, or some combination of these causes. Patients taking CellCept should have complete blood counts weekly during the first month, twice monthly for the second and third months of treatment, then monthly through the first year. If neutropenia develops (absolute neutrophil count < 1.3 x 103/µl) it may be appropriate to interrupt or discontinue CellCept. Cases of pure red cell aplasia (PRCA) have been reported in patients treated with CellCept in combination with other immunosuppressants. The mechanism for mycophenolate mofetil induced PRCA is unknown. PRCA may resolve with dose reduction or cessation of CellCept therapy. Changes to CellCept therapy should only be undertaken under appropriate supervision in transplant recipients in order to minimise the risk of graft rejection (see section 4.8). Patients receiving CellCept should be instructed to report immediately any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow depression. Patients should be advised that during treatment with CellCept, vaccinations may be less effective, and the use of live attenuated vaccines should be avoided (see section 4.5). Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Gastro-intestinal CellCept has been associated with an increased incidence of digestive system adverse events, including infrequent cases of gastrointestinal tract ulceration, haemorrhage and perforation. CellCept should be administered with caution in patients with active serious digestive system disease. CellCept is an IMPDH (inosine monophosphate dehydrogenase) inhibitor. Therefore, it should be avoided in patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndrome. Interactions Caution should be exercised when switching combination therapy from regimens containing immunosuppressants, which interfere with MPA enterohepatic recirculation e.g. ciclosporin, to others devoid of this effect e.g. sirolimus, belatacept, or vice versa, as this might result in changes of MPA exposure. Drugs of other classes which interfere with MPA's enterohepatic cycle e.g. cholesterolamine, should be used with caution due to their potential to reduce the plasma levels and efficacy of CellCept (see also section 4.5). Some degree of enterohepatic recirculation is anticipated following intravenous administration of CellCept. It is recommended that CellCept should not be administered concomitantly with azathioprine because such concomitant administration has not been studied. The risk/benefit ratio of mycophenolate mofetil in combination with tacrolimus or sirolimus has not been established (see also section 4.5). Special populations Elderly patients may be at an increased risk of adverse events such as certain infections (including cytomegalovirus tissue invasive disease) and possibly gastrointestinal haemorrhage and pulmonary oedema, compared with younger individuals (see section 4.8). Teratogenic effects Mycophenolate is a powerful human teratogen. Spontaneous abortion (rate of 45-49%) and congenital malformations (estimated rate of 23-27%) have been reported following MMF exposure during pregnancy. Therefore CellCept is contraindicated in pregnancy unless there are no suitable alternative treatments to prevent transplant rejection. Female and male patients of reproductive potential should be made aware of the risks and follow the recommendations provided in section 4.6. (e.g. contraceptive methods, pregnancy testing) prior to, during, and after therapy with CellCept. Physicians should ensure that women and men taking mycophenolate understand the risk of harm to the baby, the need for effective contraception, and the need to immediately consult their physician if there is a possibility of pregnancy. Contraception (see section 4.6) Because of the genotoxic and teratogenic potential of CellCept, women with childbearing potential should use two reliable forms of contraception simultaneously before starting CellCept therapy, during therapy, and for six weeks after stopping the therapy; unless abstinence is the chosen method of contraception (see section 4.5). Sexually active men are recommended to use condoms during treatment and for at least 90 days after cessation of treatment. Condom use applies for both reproductively competent and vasectomised men, because the risks associated with the transfer of seminal fluid also apply to men who have had a vasectomy. In addition, female partners of male patients treated with CellCept are recommended to use highly effective contraception during treatment and for a total of 90 days after the last dose of CellCept. Educational materials In order to assist patients in avoiding foetal exposure to mycophenolate and to provide additional important safety information, the Marketing Authorisation holder will provide educational materials to healthcare professionals. The educational materials will reinforce the warnings about the teratogenicity of mycophenolate, provide advice on contraception before therapy is started and guidance on the need for pregnancy testing. Full patient information about the teratogenic risk and the pregnancy prevention measures should be given by the physician to women of childbearing potential and, as appropriate, to male patients. Additional precautions Patients should not donate blood during therapy or for at least 6 weeks following discontinuation of mycophenolate. Men should not donate semen during therapy or for 90 days following discontinuation of mycophenolate. 4.5 Interaction with other medicinal products and other forms of interaction Aciclovir Higher aciclovir plasma concentrations were observed when mycophenolate mofetil was administered with aciclovir in comparison to the administration of aciclovir alone. The changes in MPAG (the phenolic glucuronide of MPA) pharmacokinetics (MPAG increased by 8%) were minimal and are not considered clinically significant. Because MPAG plasma concentrations are increased in the presence of renal impairment, as are aciclovir concentrations, the potential exists for mycophenolate mofetil and aciclovir, or its prodrugs, e.g. valaciclovir, to compete for tubular secretion, and further increases in concentrations of both substances may occur. Cholestyramine Following single dose, oral administration of 1.5 g of mycophenolate mofetil to normal healthy subjects pre-treated with 4 g TID of cholestyramine for 4 days, there was a 40% reduction in the AUC of MPA (see section 4.4, and section 5.2). Caution should be used during concomitant administration because of the potential to reduce efficacy of CellCept. Medicinal products that interfere with enterohepatic circulation Caution should be used with medicinal products that interfere with enterohepatic circulation because of their potential to reduce the efficacy of CellCept. Ciclosporin A Ciclosporin A (CsA) pharmacokinetics are unaffected by mycophenolate mofetil. In contrast, if concomitant ciclosporin treatment is stopped, an increase in MPA AUC of around 30% should be expected. CsA interferes with MPA enterohepatic recycling, resulting in reduced MPA exposures by 30-50% in renal transplant patients treated with CellCept and CsA compared with patients receiving sirolimus or belatacept and similar doses of CellCept (see also section 4.4). Conversely, changes of MPA exposure should be expected when switching patients from CsA to one of the immunosuppressants which does not interfere with MPA´s enterohepatic cycle. Telmisartan Concomitant administration of telmisartan and CellCept resulted in an approximately 30% decrease of MPA concentrations. Telmisartan changes MPA's elimination by enhancing PPAR gamma (peroxisome proliferator-activated receptor gamma) expression, which in turn results in an enhanced UGT1A9 expression and activity. When comparing rates of transplant rejection, rates of graft loss or adverse event profiles between CellCept patients with and without concomitant telmisartan medication, no clinical consequences of the pharmacokinetic drug-drug interaction were seen. Ganciclovir Based on the results of a single dose administration study of recommended doses of oral mycophenolate and IV ganciclovir and the known effects of renal impairment on the pharmacokinetics of CellCept (see section 4.2) and ganciclovir, it is anticipated that co-administration of these agents (which compete for mechanisms of renal tubular secretion) will result in increases in MPAG and ganciclovir concentration. No substantial alteration of MPA pharmacokinetics is anticipated and CellCept dose adjustment is not required. In patients with renal impairment in whom CellCept and ganciclovir or its prodrugs, e.g. valganciclovir, are co-administered, the dose recommendations for ganciclovir should be observed and patients should be monitored carefully. Oral contraceptives The pharmacokinetics and pharmacodynamics of oral contraceptives were unaffected by co-administration of CellCept (see also section 5.2). Rifampicin In patients not also taking ciclosporin, concomitant administration of CellCept and rifampicin resulted in a decrease in MPA exposure (AUC0-12h) of 18% to 70%. It is recommended to monitor MPA exposure levels and to adjust CellCept doses accordingly to maintain clinical efficacy when rifampicin is administered concomitantly. Sevelamer Decrease in MPA Cmax and AUC (0-12h) by 30% and 25%, respectively, were observed when CellCept was concomitantly administered with sevelamer without any clinical consequences (i.e. graft rejection). It is recommended, however, to administer CellCept at least one hour before or three hours after sevelamer intake to minimise the impact on the absorption of MPA. There are no data on CellCept with phosphate binders other than sevelamer. Trimethoprim/sulfamethoxazole No effect on the bioavailability of MPA was observed. Norfloxacin and metronidazole In healthy volunteers, no significant interaction was observed when CellCept was concomitantly administered with norfloxacin or metronidazole separately. However, norfloxacin and metronidazole combined reduced the MPA exposure by approximately 30% following a single dose of CellCept. Ciprofloxacin and amoxicillin plus clavulanic acid Reductions in pre-dose (trough) MPA concentrations of about 50% have been reported in renal transplant recipients in the days immediately following commencement of oral ciprofloxacin or amoxicillin plus clavulanic acid. This effect tended to diminish with continued antibiotic use and to cease within a few days of antibiotic discontinuation. The change in predose level may not accurately represent changes in overall MPA exposure. Therefore, a change in the dose of CellCept should not normally be necessary in the absence of clinical evidence of graft dysfunction. However, close clinical monitoring should be performed during the combination and shortly after antibiotic treatment. Tacrolimus In hepatic transplant patients initiated on CellCept and tacrolimus, the AUC and Cmax of MPA, the active metabolite of CellCept, were not significantly affected by co-administration with tacrolimus. In contrast, there was an increase of approximately 20% in tacrolimus AUC when multiple doses of CellCept (1.5 g BID) were administered to hepatic transplant patients taking tacrolimus. However, in renal transplant patients, tacrolimus concentration did not appear to be altered by CellCept (see also section 4.4). Other interactions Co-administration of probenecid with mycophenolate mofetil in monkeys raises plasma AUC of MPAG by 3-fold. Thus, other substances known to undergo renal tubular secretion may compete with MPAG, and thereby raise plasma concentrations of MPAG or the other substance undergoing tubular secretion. Live vaccines Live vaccines should not be given to patients with an impaired immune response. The antibody response to other vaccines may be diminished (see also section 4.4). Paediatric population Interaction studies have only been performed in adults. 4.6 Pregnancy and lactation Contraception in males and females CellCept is contraindicated in women of childbearing potential who are not using highly effective contraception. Because of the genotoxic and teratogenic potential of CellCept, women with childbearing potential should use two reliable forms of contraception simultaneously before beginning CellCept therapy, during therapy, and for six weeks following discontinuation of therapy; unless abstinence is the chosen method of contraception (see section 4.5). Sexually active men are recommended to use condoms during treatment and for at least 90 days after cessation of treatment. Condom use applies for both reproductively competent and vasectomised men, because the risks associated with the transfer of seminal fluid also apply to men who have had a vasectomy. In addition, female partners of male patients treated with CellCept are recommended to use highly effective contraception during treatment and for a total of 90 days after the last dose of CellCept. Pregnancy CellCept is contraindicated during pregnancy unless there is no suitable alternative treatment to prevent transplant rejection. Treatment should not be initiated without providing a negative pregnancy test result to rule out unintended use in pregnancy. Female and male patients of reproductive potential must be made aware of the increased risk of pregnancy loss and congenital malformations at the beginning of the treatment and must be counselled regarding pregnancy prevention, and planning. Before starting CellCept treatment, women of child bearing potential should have a pregnancy test in order to exclude unintended exposure of the embryo to mycophenolate. Two serum or urine pregnancy tests with a sensitivity of at least 25 mIU/mL are recommended; the second test should be performed 8 – 10 days after the first one and immediately before starting mycophenolate mofetil. Pregnancy tests should be repeated as clinically required (e.g. after any gap in contraception is reported). Results of all pregnancy tests should be discussed with the patient. Patients should be instructed to consult their physician immediately should pregnancy occur. Mycophenolate is a powerful human teratogen, with an increased risk of spontaneous abortions and congenital malformations in case of exposure during pregnancy; • Spontaneous abortions have been reported in 45 to 49% of pregnant women exposed to mycophenolate mofetil, compared to a reported rate of between 12 and 33% in solid organ transplant patients treated with immunosuppressants other than mycophenolate mofetil. • Based on literature reports, malformations occurred in 23 to 27% of live births in women exposed to mycophenolate mofetil during pregnancy (compared to 2 to 3 % of live births in the overall population and approximately 4 to 5% of live births in solid organ transplant recipients treated with immunosuppressants other than mycophenolate mofetil). Congenital malformations, including reports of multiple malformations, have been observed post-marketing in children of patients exposed to CellCept during pregnancy in combination with other immunosuppressants. The following malformations were most frequently reported: • Abnormalities of the ear (e.g. abnormally formed or absent external/middle ear), external auditory canal artesia; • Congenital heart disease such as atrial and ventricular septal defects; • Facial malformations such as cleft lip, cleft palate, micrognathia and hypertelorism of the orbits; • Abnormalities of the eye (e.g. coloboma); • Malformations of the fingers (e.g. polydactyly, syndactyly); • Tracheo-Oesophageal malformations (e.g. oesophageal atresia); • Nervous system malformations such as spina bifida; • Renal abnormalities. In addition there have been isolated reports of the following malformations: • Microphthalmia; • congenital choroid plexus cyst; • septum pellucidum agenesis; • olfactory nerve agenesis. Studies in animals have shown reproductive toxicity (see section 5.3). Breast-feeding Mycophenolate mofetil has been shown to be excreted in the milk of lactating rats. It is not known whether this substance is excreted in human milk. Because of the potential for serious adverse reactions to mycophenolate mofetil in breast-fed infants, CellCept is contraindicated in nursing mothers (see section 4.3). 4.7 Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed. The pharmacodynamic profile and the reported adverse reactions indicate that an effect is unlikely. 4.8 Undesirable effects The following undesirable effects cover adverse reactions from clinical trials The principal adverse reactions associated with the administration of CellCept in combination with ciclosporin and corticosteroids include diarrhoea, leucopenia, sepsis and vomiting, and there is evidence of a higher frequency of certain types of infections (see section 4.4). The adverse reaction profile associated with the administration of CellCept 500 mg powder for concentrate for solution for infusion has been shown to be similar to that observed after oral administration. Malignancies Patients receiving immunosuppressive regimens involving combinations of medicinal products, including CellCept, are at increased risk of developing lymphomas and other malignancies, particularly of the skin (see section 4.4). Lymphoproliferative disease or lymphoma developed in 0.6% of patients receiving CellCept (2 g or 3 g daily) in combination with other immunosuppressants in controlled clinical trials of renal (2 g data), cardiac and hepatic transplant patients followed for at least 1 year. Non-melanoma skin carcinomas occurred in 3.6% of patients; other types of malignancy occurred in 1.1% of patients. Three-year safety data in renal and cardiac transplant patients did not reveal any unexpected changes in incidence of malignancy compared to the 1-year data. Hepatic transplant patients were followed for at least 1 year, but less than 3 years. Opportunistic infections All transplant patients are at increased risk of opportunistic infections; the risk increased with total immunosuppressive load (see section 4.4). The most common opportunistic infections in patients receiving CellCept (2 g or 3 g daily) with other immunosuppressants in controlled clinical trials of renal (2 g data), cardiac and hepatic transplant patients followed for at least 1 year were candida mucocutaneous, CMV viraemia/syndrome and Herpes simplex. The proportion of patients with CMV viraemia/syndrome was 13.5%. Elderly : Elderly patients (≥ 65 years) may generally be at increased risk of adverse reactions due to immunosuppression. Elderly patients receiving CellCept as part of a combination immunosuppressive regimen, may be at increased risk of certain infections (including cytomegalovirus tissue invasive disease) and possibly gastrointestinal haemorrhage and pulmonary oedema, compared to younger individuals. Other adverse reactions The following data refer to the safety experience of oral CellCept in renal transplant patients. Data in hepatic transplant patients are based on i.v. dosing of CellCept for up to 14 days followed by oral dosing. Adverse reactions, probably or possibly related to CellCept, reported in ≥1/10 and in ≥1/100 to <1/10 of patients treated with CellCept in the controlled clinical trials of renal (2 g data) and hepatic transplant patients are listed in the following table. Adverse Reactions, Probably or Possibly Related to CellCept, Reported in Patients Treated with CellCept in Renal and Hepatic Clinical Trials when Used in Combination with Ciclosporin and Corticosteroids Within the system organ classes, undesirable effects are listed under headings of frequency, using the following categories: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. System organ class Adverse drug reactions Infections and infestations Very common Sepsis, gastrointestinal candidiasis, urinary tract infection, herpes simplex, herpes zoster Common Pneumonia, influenza, respiratory tract infection, respiratory moniliasis, gastrointestinal infection, candidiasis, gastroenteritis, infection, bronchitis, pharyngitis, sinusitis, fungal skin infection, skin candida, vaginal candidiasis, rhinitis Neoplasms benign, malignant and unspecified (incl cysts and polyps) Very common - Common Skin cancer, benign neoplasm of skin Blood and lymphatic system disorders Very common Leucopenia, thrombocytopenia, anaemia Common Pancytopenia, leukocytosis Metabolism and nutrition disorders Very common - Common Acidosis, hyperkalaemia, hypokalaemia, hyperglycaemia, hypomagnesaemia, hypocalcaemia, hypercholesterolaemia, hyperlipidaemia, hypophosphataemia, anorexia Psychiatric disorders Very common - Common Depression, thinking abnormal, insomnia Nervous system disorders Very common - Common Convulsion, hypertonia, tremor, somnolence, headache, paraesthesia Cardiac disorders Very common - Common Tachycardia Vascular disorders Very common - Common Hypotension, hypertension Respiratory, thoracic and mediastinal disorders Very common - Common Pleural effusion, dyspnoea, cough Gastrointestinal disorders Very common Vomiting, abdominal pain, diarrhoea, nausea Common Gastrointestinal haemorrhage, peritonitis, ileus, colitis, gastric ulcer, duodenal ulcer, gastritis, oesophagitis, stomatitis, constipation, dyspepsia, flatulence Hepatobiliary disorders Very common - Common Hepatitis Skin and subcutaneous tissue disorders Very common - Common Rash, acne, alopecia, Musculoskeletal and connective Tissue disorders Very common - Common Arthralgia Renal and urinary disorders Very common - Common Renal impairment General disorders and administration site conditions Very common - Common Oedema, pyrexia, chills, pain, malaise, asthenia, Investigations Very common - Common Hepatic enzyme increased, blood creatinine increased, blood lactate dehydrogenase increased, blood alkaline phosphatase increased, weight decreased Note: 501 (2 g CellCept daily) and 277 (2 g IV / 3 g oral CellCept daily) patients were treated in Phase III studies for the prevention of rejection in renal and hepatic transplantation, respectively. Adverse reactions attributable to peripheral venous infusion were phlebitis and thrombosis, both observed at 4% in patients treated with CellCept 500 mg powder for concentrate for solution for infusion. The following undesirable effects cover adverse reactions from post-marketing experience Adverse reactions reported during post-marketing with CellCept are similar to those seen in the controlled renal and hepatic transplant studies. Additional adverse reactions reported during post-marketing experience with CellCept are described below with the frequencies reported within brackets if known. Gastrointestinal Gingival hyperplasia (≥1/100 to <1/10), colitis including cytomegalovirus colitis, (≥1/100 to <1/10), pancreatitis (≥1/100 to <1/10) and intestinal villous atrophy. Infections Serious life-threatening infections including meningitis, endocarditis tuberculosis and atypical mycobacterial infection. Cases of BK virus associated nephropathy, as well as cases of JC virus associated progressive multifocal leucoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including CellCept. Agranulocytosis (≥1/1000 to <1/100) and neutropenia have been reported; therefore regular monitoring of patients taking CellCept is advised (see section 4.4). There have been reports of aplastic anaemia and bone marrow depression in patients treated with CellCept, some of which have been fatal. Blood and lymphatic system disorder Cases of pure red cell aplasia (PRCA) have been reported in patients treated with CellCept (see section 4.4). Isolated cases of abnormal neutrophil morphology, including the acquired Pelger-Huet anomaly, have been observed in patients treated with CellCept. These changes are not associated with impaired neutrophil function. These changes may suggest a 'left shift' in the maturity of neutrophils in haematological investigations, which may be mistakenly interpreted as a sign of infection in immunosuppressed patients such as those that receive CellCept. Hypersensitivity Hypersensitivity reactions, including angioneurotic oedema and anaphylactic reaction, have been reported. Pregnancy, puerperium and perinatal conditions Cases of spontaneous abortions have been reported in patients exposed to mycophenolate mofetil, mainly in the first trimester, see section 4.6. Congenital disorders Congenital malformations have been observed post-marketing in children of patients exposed to CellCept in combination with other immunosuppressants, see section 4.6. Respiratory, thoracic and mediastinal disorders There have been isolated reports of interstitial lung disease and pulmonary fibrosis in patients treated with CellCept in combination with other immunosuppressants, some of which have been fatal. There have also been reports of bronchiectasis in children and adults (frequency not known). Immune system disorders Hypogammaglobulinaemia has been reported in patients receiving CellCept in combination with other immunosuppressants (frequency not known). Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation 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 (see details below). Ireland HPRA Pharmacovigilance Earlsfort Terrace IRL - Dublin 2 Tel: +353 1 6764971 Fax: +353 1 6762517 Website: www.hpra.ie e-mail: medsafety@hpra.ie Malta ADR Reporting Website: www.medicinesauthority.gov.mt/adrportal United Kingdom Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard 4.9 Overdose Reports of overdoses with mycophenolate mofetil have been received from clinical trials and during post-marketing experience. In many of these cases, no adverse events were reported. In those overdose cases in which adverse events were reported, the events fall within the known safety profile of the medicinal product. It is expected that an overdose of mycophenolate mofetil could possibly result in over suppression of the immune system and increase susceptibility to infections and bone marrow suppression (see section 4.4). If neutropenia develops, dosing with CellCept should be interrupted or the dose reduced (see section 4.4). Haemodialysis would not be expected to remove clinically significant amounts of MPA or MPAG. Bile acid sequestrants, such as cholestyramine, can remove MPA by decreasing the enterohepatic re-circulation of the drug (see section 5.2). 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: immunosuppressive agents ATC code L04AA06 Mechanism of action Mycophenolate mofetil is the 2-morpholinoethyl ester of MPA. MPA is a potent, selective, uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase, and therefore inhibits the de novo pathway of guanosine nucleotide synthesis without incorporation into DNA. Because T- and B-lymphocytes are critically dependent for their proliferation on de novo synthesis of purines whereas other cell types can utilise salvage pathways, MPA has more potent cytostatic effects on lymphocytes than on other cells. 5.2 Pharmacokinetic properties Distribution Following intravenous administration, mycophenolate mofetil undergoes rapid and complete metabolism to the active metabolite, MPA. The parent substance mycophenolate mofetil can be measured systemically during intravenous infusion. MPA at clinically relevant concentrations is 97% bound to plasma albumin. As a result of enterohepatic recirculation, secondary increases in plasma MPA concentration are usually observed at approximately 6 – 12 hours post-dose. A reduction in the AUC of MPA of approximately 40% is associated with the co-administration of cholestyramine (4 g TID), indicating that there is a significant amount of enterohepatic recirculation. Biotransformation MPA is metabolised principally by glucuronyl transferase (isoform UGT1A9) to form the inactive phenolic glucuronide of MPA (MPAG). In vivo, MPAG is converted back to free MPA via enterohepatic recirculation. A minor acylglucuronide (AcMPAG) is also formed. AcMPAG is pharmacologically active and is suspected to be responsible for some of MMF´s side effects (diarrhoea, leucopenia). Elimination A negligible amount of substance is excreted as MPA (< 1% of dose) in the urine. Oral administration of radiolabelled mycophenolate mofetil results in complete recovery of the administered dose, with 93% of the administered dose recovered in the urine and 6% recovered in faeces. Most (about 87%) of the administered dose is excreted in the urine as MPAG. At clinically encountered concentrations, MPA and MPAG are not removed by haemodialysis. However, at high MPAG plasma concentrations (> 100µg/mL), small amounts of MPAG are removed. By interfering with enterohepatic circulation of the drug, bile acid sequestrants such as cholestyramine, reduce MPA AUC (see section 4.9). MPA's disposition depends on several transporters. Organic anion-transporting polypeptides (OATPs) and multidrug resistance-associated protein 2 (MRP2) are involved in MPA's disposition; OATP isoforms, MRP2 and breast cancer resistance protein (BCRP) are transporters associated with the glucuronides' biliary excretion. Multidrug resistance protein 1 (MDR1) is also able to transport MPA, but its contribution seems to be confined to the absorption process. In the kidney MPA and its metabolites potently interact with renal organic anion transporters. In the early post-transplant period (< 40 days post-transplant), renal, cardiac and hepatic transplant patients had mean MPA AUCs approximately 30% lower and Cmax approximately 40% lower compared to the late post-transplant period (3 – 6 months post-transplant). Equivalence with oral dosage forms MPA AUC values obtained following administration of 1 g BID intravenous CellCept to renal transplant patients in the early post-transplant phase are comparable to those observed following 1 g BID oral CellCept. In hepatic transplant patients, administration of 1 g BID intravenous CellCept followed by 1.5 g BID oral CellCept resulted in MPA AUC values similar to those found in renal transplant patients administered 1 g CellCept BID. Special populations Renal impairment In a single dose study (6 subjects/group), mean plasma MPA AUC observed in subjects with severe chronic renal impairment (glomerular filtration rate < 25 mL/min/1.73 m2) were 28 – 75% higher relative to the means observed in normal healthy subjects or subjects with lesser degrees of renal impairment. However, the mean single dose MPAG AUC was 3 – 6 fold higher in subjects with severe renal impairment than in subjects with mild renal impairment or normal healthy subjects, consistent with the known renal elimination of MPAG. Multiple dosing of mycophenolate mofetil in patients with severe chronic renal impairment has not been studied. No data are available for hepatic transplant patients with severe chronic renal impairment. Delayed renal graft function In patients with delayed renal graft function post-transplant, mean MPA AUC (0–12h) was comparable to that seen in post-transplant patients without delayed graft function. Mean plasma MPAG AUC (0-12h) was 2 – 3-fold higher than in post-transplant patients without delayed graft function. There may be a transient increase in the free fraction and concentration of plasma MPA in patients with delayed renal graft function. Dose adjustment of CellCept does not appear to be necessary. Hepatic impairment In volunteers with alcoholic cirrhosis, hepatic MPA glucuronidation processes were relatively unaffected by hepatic parenchymal disease. Effects of hepatic disease on this process probably depend on the particular disease. However, hepatic disease with predominantly biliary damage, such as primary biliary cirrhosis, may show a different effect. Elderly: Pharmacokinetic behaviour of CellCept in the elderly (≥ 65 years) has not been formally evaluated. Patients taking oral contraceptives The pharmacokinetics of oral contraceptives were unaffected by co-administration of CellCept (see also section 4.5). A study of the co-administration of CellCept (1 g bid) and combined oral contraceptives containing ethinylestradiol (0.02 mg to 0.04 mg) and levonorgestrel (0.05 mg to 0.15 mg), desogestrel (0.15 mg) or gestodene (0.05 mg to 0.10 mg) conducted in 18 non-transplant women (not taking other immunosupressants) over 3 consecutive menstrual cycles showed no clinically relevant influence of CellCept on the ovulation suppressing action of the oral contraceptives. Serum levels of LH, FSH and progesterone were not significantly affected. 5.3 Preclinical safety data In experimental models, mycophenolate mofetil was not tumourigenic. The highest dose tested in the animal carcinogenicity studies resulted in approximately 2 – 3 times the systemic exposure (AUC or Cmax) observed in renal transplant patients at the recommended clinical dose of 2 g/day. Two genotoxicity assays (in vitro mouse lymphoma assay and in vivo mouse bone marrow micronucleus test) showed a potential of mycophenolate mofetil to cause chromosomal aberrations. These effects can be related to the pharmacodynamic mode of action, i.e. inhibition of nucleotide synthesis in sensitive cells. Other in vitro tests for detection of gene mutation did not demonstrate genotoxic activity. Mycophenolate mofetil had no effect on fertility of male rats at oral doses up to 20 mg/kg/day. The systemic exposure at this dose represents 2 – 3 times the clinical exposure at the recommended clinical dose of 2 g/day. In a female fertility and reproduction study conducted in rats, oral doses of 4.5 mg/kg/day caused malformations (including anophthalmia, agnathia, and hydrocephaly) in the first generation offspring in the absence of maternal toxicity. The systemic exposure at this dose was approximately 0.5 times the clinical exposure at the recommended clinical dose of 2 g/day. No effects on fertility or reproductive parameters were evident in the dams or in the subsequent generation. In teratology studies in rats and rabbits, foetal resorptions and malformations occurred in rats at 6 mg/kg/day (including anophthalmia, agnathia, and hydrocephaly) and in rabbits at 90 mg/kg/day (including cardiovascular and renal anomalies, such as ectopia cordis and ectopic kidneys, and diaphragmatic and umbilical hernia), in the absence of maternal toxicity. The systemic exposure at these levels is approximately equivalent to or less than 0.5 times the clinical exposure at the recommended clinical dose of 2 g/day (see section 4.6). The haematopoietic and lymphoid systems were the primary organs affected in toxicology studies conducted with mycophenolate mofetil in the rat, mouse, dog and monkey. These effects occurred at systemic exposure levels that are equivalent to or less than the clinical exposure at the recommended dose of 2 g/day. Gastrointestinal effects were observed in the dog at systemic exposure levels equivalent to or less than the clinical exposure at the recommended dose. Gastrointestinal and renal effects consistent with dehydration were also observed in the monkey at the highest dose (systemic exposure levels equivalent to or greater than clinical exposure). The nonclinical toxicity profile of mycophenolate mofetil appears to be consistent with adverse events observed in human clinical trials which now provide safety data of more relevance to the patient population (see section 4.8). 6. Pharmaceutical particulars 6.1 List of excipients CellCept 500 mg powder for concentrate for solution for infusion polysorbate 80 citric acid hydrochloric acid sodium chloride 6.2 Incompatibilities CellCept 500 mg powder for concentrate for solution for infusion solution should not be mixed or administered concurrently via the same catheter with other intravenous medicinal products or infusion admixtures. This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6. 6.3 Shelf life Powder for concentrate for solution for infusion: 3 years. Reconstituted solution and infusion solution: If the infusion solution is not prepared immediately prior to administration, the commencement of administration of the infusion solution should be within 3 hours from reconstitution and dilution of the medicinal product. 6.4 Special precautions for storage Powder for concentrate for solution for infusion: Do not store above 30 °C. Reconstituted solution and infusion solution: Store at 15 – 30°C. 6.5 Nature and contents of container 20 mL type I clear glass vials with grey butyl rubber stopper and aluminium seals with plastic flip-off caps. CellCept 500 mg powder for concentrate for solution for infusion is available in packs containing 4 vials. 6.6 Special precautions for disposal and other handling Preparation of Infusion Solution (6 mg/mL) CellCept 500 mg powder for concentrate for solution for infusion does not contain an antibacterial preservative; therefore, reconstitution and dilution of the product must be performed under aseptic conditions. CellCept 500 mg powder for concentrate for solution for infusion must be prepared in two steps: the first step is a reconstitution step with glucose intravenous infusion 5% and the second step is a dilution step with glucose intravenous infusion 5%. A detailed description of the preparation is given below: Step 1 a. Two vials of CellCept 500 mg powder for concentrate for solution for infusion are used for preparing each 1 g dose. Reconstitute the content of each vial by injecting 14 mL of glucose intravenous infusion 5%. b. Gently shake the vial to dissolve the medicinal product yielding a slightly yellow solution. c. Inspect the resulting solution for particulate matter and discoloration prior to further dilution. Discard the vial if particulate matter or discoloration is observed. Step 2 a. Further dilute the content of the two reconstituted vials (approx. 2 x 15 mL) into 140 mL of glucose intravenous infusion 5%. The final concentration of the solution is 6 mg/mL mycophenolate mofetil. b. Inspect the infusion solution for particulate matter or discoloration. Discard the infusion solution if particulate matter or discoloration is observed. If the infusion solution is not prepared immediately prior to administration, the commencement of administration of the infusion solution should be within 3 hours from reconstitution and dilution of the medicinal product. Keep solutions at 15 – 30° C. Any unused product or waste material should be disposed of in accordance with local requirements. 7. Marketing authorisation holder Roche Registration Limited 6 Falcon Way Shire Park Welwyn Garden City AL7 1TW United Kingdom 8. Marketing authorisation number(s) EU/1/96/005/005 CellCept (4 vials) 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 14 February 1996 Date of latest renewal: 13 March 2006 10. Date of revision of the text 27 November 2015 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/ ------------------------------------------------------ 产地国家：英国 原产地英文商品名: Cellcept powder solution for infusion  500mg/20ML/Vial 4vials/box 原产地英文药品名: Mycophenolate Mofetil 中文参考商品译名: 骁悉粉末注射溶液 500毫克/20毫升/瓶，4瓶/盒 中文参考药品译名: 霉酚酸酯  生产厂家中文参考译名: 罗氏制药 生产厂家英文名: Roche Products ------------------------------------------------------ 产地国家：美国 原产地英文商品名: Cellcept Injection 500mg/20ML/Vial 4vials/box 原产地英文药品名: Mycophenolate Mofetil 中文参考商品译名: 骁悉注射剂 500毫克/20毫升/瓶，4瓶/盒 中文参考药品译名: 霉酚酸酯  生产厂家中文参考译名: GENENTECH USA ROCHE 生产厂家英文名: GENENTECH USA ROCHE https://www.drugs.com/pro/cellcept.html