卡莫司汀植入膜剂(Gliadel)—为全球首个治疗脑癌的植入膜剂 Gliadel为一种白色至灰白色的一角硬币大小的薄膜，包含生物可降解聚合物聚苯丙生20和7.7mg卡莫司汀（carmustine，BCNU），卡莫司汀是治疗恶性胶质瘤的常用静脉给药的化疗药物。 当手术切除脑瘤时，在经手术创建的空腔中可最多植入8片本品。在植入处，Gliadel将缓慢溶解，直接向肿瘤部位释放高浓度卡莫司汀，使扩撒到其它部位的药物减至最少。  Gliadel适应证是新诊断为高度恶性胶质瘤的患者的手术和放疗辅助药物，也可作为多形性胶质母细胞瘤（GBM）复发患者的手术辅助用药。  Polifeprosan 20 with Carmustine Implant Gliadel Wafer格立得植入剂 成分及性状 Gliadel Wafer为直径1.45公分、厚约1公厘的灰白至淡黄色无菌植入製剂。每一片含可生物分解的聚酸酐polifeprosan 20 (polyanhydride copolymer) 192.3 毫克及carmustine 7.7 毫克。Carmustine均匀分布於polifeprosan 20基质中，并由prolifeprosan 20负责控制carmustine的局部传送。 作用 Gliadel Wafer能够直接将carmustine释放至脑癌摘除手术后所造成的腔室内，并扩散至週边的脑组织，藉由对DNA及RNA的烷基化作用而发挥抗惡性肿瘤作用。 药物动力学 Gliadel Wafer中的polifeprosan 20，在动物实验中发现，超过70%於三週内分解，分解后的单体包括carboxyphenoxypropane经由肾臟排除，而sebacic acid则经由肝臟代谢成二氧化碳排出体外。Prolifeprosan 20 在人体内的吸收、分佈、代谢及排除等特性尚不清楚。Gliadel Wafer释放至人体脑腔的carmustine浓度也尚无测量值。 植入脑癌摘除手术后腔室的Gliadel Wafer能被生物分解，分解率因人而異。 即使所有成分皆被充分分解，但於分解过程中，脑部影像扫瞄或再次手术皆可見到植入剂残餘物尚留在脑内。 适应症 作为復发性多形性神经胶母细胞瘤病人的手术辅助。 不良反应 1. 癲癇发作：高度惡性神经胶质瘤復发病人之再次手术臨床试验发现，兩组病人的癲癇发作率为19%，手术后五天内癲癇发作的发生率为54% (12/22，Gliadel Wafer组)及9% (2/22，安慰剂组)。手术后第一次癲癇发作时间的平均天數为Gliadel Wafer组3.5天，安慰剂组61天。 2. 脑水肿：新诊断罹患高度惡性神经胶质瘤病人之手术治療臨床试验显示，脑水肿发生率为22.5% (Gliadel Wafer组)及19.2%(安慰剂组)。脑水肿伴随肿块时(可能原因有肿瘤復发、颅内感染、坏死)，可能需要再次手术，有些病人甚至必须取出Gliadel Wafer或其残留物。 3. 伤口癒合異常：高度惡性神经胶质瘤復发病人之再次手术臨床试验，伤口癒合異常发生率为14%(Gliadel Wafer组)及5%(安慰剂组)。 4. 颅内感染：高度惡性神经胶质瘤復发病人之再次手术臨床试验中，脑脓疡或脑膜炎的发生率为4%(Gliadel Wafer组) 及1%( 安慰剂组)。 注意事项 手术摘除后的腔室应避免与脑室相通，以预防Gliadel Wafer移位至脑室，造成阻塞性水脑。如肿瘤摘除后之腔室与脑室之缺口大於Gliadel Wafer的直径， 应填补缺口后再植入GliadelWafer。 禁忌 已知对carmustine或本药品其它任一成分过敏的病人禁忌投与Gliadel Wafer。 交互作用 目前尚无Gliadel Wafer与其它药品交互作用的研究。化学治療併Gliadel Wafer的短期及长期毒性试验结果尚未完成。放射性治療併Gliadel Wafer未見任何短期或慢性毒性。 剂量及用法 每一片Gliadel Wafer含carmustine 7.7 mg，手术植入八片等於投与剂量61.6 mg。一般建议剂量：於脑癌摘除手术后所造成的腔室内植入Gliadel Wafer八片。若空间不够植入八片，则尽可能以最大能植入的片數植入。 目前尚无单次手术植入Gliadel Wafer八片以上的臨床经验，因此不建议植入八片以上。 Gliadel Wafer对儿童的安全性及有效性尚未建立。  储存 零下20°C以下。 Gliadel 7.7mg Implant 1. Name of the medicinal product GLIADEL 7.7 MG IMPLANT 2. Qualitative and quantitative composition Each implant contains 7.7 mg of carmustine. For a full list of excipients, see section 6.1. 3. Pharmaceutical form Implant Off-white to pale yellow flat discoid implant. 4. Clinical particulars 4.1 Therapeutic indications GLIADEL Implant is indicated in newly-diagnosed high-grade malignant glioma patients as an adjunct to surgery and radiation. GLIADEL Implant is indicated for use as an adjunct to surgery in patients with recurrent histologically proved glioblastoma multiforme for whom surgical resection is indicated. 4.2 Posology and method of administration For intralesional use in adults only. Each GLIADEL Implant contains 7.7 mg of carmustine, resulting in a dose of 61.6 mg when eight implants are placed in the tumour resection cavity. It is recommended that a maximum of eight implants be placed if the size and shape of the resection cavity allows it. Implants broken in half may be used, but implants broken in more than two pieces should be discarded in the dedicated biohazard waste containers (see section 6.6). It is recommended that the placement of the implants should be directly from the product's inner sterile packaging into the resection cavity. Oxidised regenerated cellulose may be placed over the implants to secure them to the cavity surface (see section 6.6). 4.3 Contraindications Hypersensitivity to the active substance carmustine or to any of the excipients of GLIADEL Implant. 4.4 Special warnings and precautions for use Patients undergoing craniotomy for glioblastoma and implantation of GLIADEL Implant should be monitored closely in view of known complications of craniotomy which includes convulsions, intracranial infections, abnormal wound healing, and brain oedema (see section 4.8). Cases of intracerebral mass effect unresponsive to corticosteroids have been described in patients treated with GLIADEL Implant, including one case leading to brain herniation. Careful monitoring of GLIADEL Implant-treated patients for cerebral oedema/intracranial hypertension with consequent steroid use is warranted (see section 4.8). CSF leak was more common in GLIADEL Implant-treated patients. Attention to a water-tight dural closure and local wound care is indicated (see section 4.8). Development of brain oedema with mass effect (due to tumour recurrence, intracranial infection, or necrosis) may necessitate re-operation and, in some cases, removal of GLIADEL Implant or its remnants. Communication between the surgical resection cavity and the ventricular system should be avoided to prevent the implants from migrating into the ventricular system and possibly causing obstructive hydrocephalus. If a communication larger than the diameter of the implant exists, it should be closed prior to GLIADEL Implant implantation. Computed tomography and magnetic resonance imaging may demonstrate enhancement in the brain tissue surrounding the resection cavity after placement of GLIADEL Implants. This enhancement may represent oedema and inflammation caused by GLIADEL Implants or tumour progression. 4.5 Interaction with other medicinal products and other forms of interaction Interactions of GLIADEL Implant with other drugs or chemotherapy have not been formally evaluated. 4.6 Pregnancy and lactation Pregnancy: There are no studies of GLIADEL Implant in pregnant women and no studies assessing the reproductive toxicity of GLIADEL Implant. Carmustine, the active component of GLIADEL Implant, when administered systemically, can have genotoxic effects and can adversely affect foetal development. GLIADEL Implant, therefore, should not be used during pregnancy. If the use of GLIADEL Implant during pregnancy is still considered, the patient should be informed of the potential risk to the foetus. Women of childbearing potential should be advised to avoid pregnancy while receiving GLIADEL Implant. In case of patients getting pregnant during treatment with GLIADEL Implant, the opportunity for genetic advice should be seized. Lactation: It is not known if GLIADEL Implant components are excreted in human milk. Since some drugs are excreted in human milk and because of the potential risk of serious adverse reactions of carmustine in nursing infants, breast-feeding is contra-indicated. 4.7 Effects on ability to drive and use machines No effects on ability to drive and use machines have been observed. However, driving is not advisable following treatment. 4.8 Undesirable effects The spectrum of undesirable effects observed in patients with newly-diagnosed high-grade malignant glioma and recurrent malignant gliomas was generally consistent with that encountered in patients undergoing craniotomy for malignant gliomas. Very common (≥ 1/10), common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1,000 to < 1/100) adverse reactions reported in patients receiving GLIADEL Implant during the clinical trials are listed below. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Primary Surgery The following data are the most frequently occurring adverse events observed in 5% or more of the 120 newly-diagnosed malignant glioma patients receiving GLIADEL Implant during the trial. Common Adverse Events Observed in ≥ 5% of Patients Receiving GLIADEL Implant at Initial Surgery Class organ Adverse events Endocrine disorders common Diabetes mellitus Metabolism and nutrition disorders very common Healing abnormal common Peripheral oedema Nervous system disorders very common Hemiplegia, convulsion, confusion, brain oedema, aphasia, depression, somnolence, speech disorder common Amnesia, intracranial hypertension, personality disorder, anxiety, facial paralysis, neuropathy, ataxia, hypoesthesia, paresthesia, thinking abnormal, abnormal gait, dizziness, grand mal convulsion, hallucinations, insomnia, tremor Eye disorders common Conjonctival oedema, abnormal vision, visual field defect Cardiac disorders very common Deep thrombophlebitis common Pulmonary embolism, haemorrhage Respiratory, thoracic and mediastinal disorders common Pneumonia Gastrointestinal disorders very common Nausea, vomiting, constipation common Diarrhoea Skin and subcutaneous tissue disorders very common Rash, alopecia Renal and urinary disorders common Urinary tract infection, urinary incontinence General disorders and administration site conditions very common Aggravation reaction, headache, asthenia, infection, fever, pain common Abdominal pain, back pain, face oedema, chest pain, abscess, accidental injury Intracranial hypertension was present in more GLIADEL Implant-treated patients than in Placebo patients (9.2% vs. 1.7%). It was typically observed late, at the time of tumour recurrence, and was unlikely to be associated with GLIADEL Implant use (see section 4.4). CSF leak was more common in GLIADEL Implant-treated patients than in placebo patients. However intracranial infections and other healing abnormalities were not increased (see section 4.4). Surgery for Recurrent Disease The following post-operative adverse events were observed in 4% or more of the 110 patients receiving GLIADEL Implant at recurrent surgery in a controlled clinical trial. Except for nervous system effects, where there is a possibility that the placebo implants could have been responsible, only events more common in the GLIADEL Implant group are listed. These adverse events were either not present pre-operatively or worsened post-operatively during the follow-up period. The follow-up period was up to 71 months. Common Adverse Events in ≥4% of Patients Receiving GLIADEL Implant at Recurrent Surgery Class organ Adverse events Blood and lymphatic system disorders common Anaemia Metabolism and nutrition disorders very common Healing abnormal common Hyponatraemia Nervous system disorders very common Convulsion, hemiplegia, headache, somnolence, confusion common Aphasia, stupor, brain oedema, intracranial hypertension, meningitis or abscess Cardiac disorders common Deep thrombophlebitis, Pulmonary embolism Respiratory, thoracic and mediastinal disorders common Pneumonia Gastrointestinal disorders common Nausea, nausea and vomiting, oral moniliasis Skin and subcutaneous tissue disorders common Rash Renal and urinary disorders very common Urinary tract infection General disorders and administration site conditions very common Fever common Infection, pain The following adverse events, not listed in the table above, were reported in less than 4% but at least 1% of patients treated with GLIADEL Implant in all studies. The events listed were either not present pre-operatively or worsened post-operatively. Whether GLIADEL Implant caused these events cannot be determined. Common Adverse Events in 1% to 4% of Patients Receiving GLIADEL Implant Class organ Adverse events Blood and lymphatic system disorders common Thrombocytopenia, leukocytosis Metabolism and nutrition disorders common Hyponatraemia, hyperglycaemia, hypokalaemia Nervous system disorders common Hydrocephalus, depression, abnormal thinking, ataxia, dizziness, insomnia, hemiplegia, coma, amnesia, diplopia, paranoid reaction uncommon Cerebral haemorrhage, cerebral infarct Eye Disorders common Visual defect, eye pain Cardiac and vascular Disorders common Hypertension, hypotension Respiratory, thoracic and mediastinal disorders common Infection, aspiration pneumonia Gastrointestinal disorders common Diarrhoea, constipation, dysphagia, gastrointestinal haemorrhage, faecal incontinence Skin and subcutaneous tissue disorders common Rash Musculoskeletal and connective tissue disorders common Infection Renal and urinary disorders common Urinary incontinence General disorders and administration site conditions common Peripheral oedema, neck pain, accidental injury, back pain, allergic reaction, asthenia, chest pain, sepsis The following four categories of adverse events are possibly related to treatment with GLIADEL Implant. Seizures: In the initial surgery trial, the incidence of seizures within the first 5 days after implantation was 2.5% in the GLIADEL Implant group. In the surgery for recurrent disease trial, the incidence of post-operative seizures was 19% in patients receiving GLIADEL Implant. 12/22 (54%) of patients treated with GLIADEL Implant experienced the first new or worsened seizure within the first five post-operative days. The median time to onset of the first new or worsened post-operative seizure was 3.5 days in patients treated with GLIADEL Implant. Brain Oedema: Development of brain oedema with mass effect (due to tumour recurrence, intracranial infection, or necrosis) may necessitate re-operation and, in some cases, removal of GLIADEL Implant or its remnants (see section 4.4). Healing Abnormalities: The following healing abnormalities have been reported in clinical trials of GLIADEL Implant: wound dehiscence, delayed wound healing, subdural, subgaleal or wound effusions, and cerebrospinal fluid leak. In the initial surgery trial, cerebrospinal fluid leaks occurred in 5% of GLIADEL Implant recipients. During surgery, a water-tight dural closure should be obtained to minimise the risk of cerebrospinal fluid leak (see section 4.4) Intracranial Infection: In the initial surgery trial, the incidence of brain abscess or meningitis was 5% in patients treated with GLIADEL Implant. In the recurrent setting, the incidence of brain abscess or meningitis was 4% in patients treated with GLIADEL Implant. In a published clinical study, cyst formation after GLIADEL Implant treatment has been reported. This reaction occurred in 10% of the patients observed in the study, however, the formation of cysts is possible after resection of a malignant glioma. 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 via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard 4.9 Overdose Not applicable. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antineoplastic agents, ATC Code: L01AD0I Preclinical data GLIADEL Implant delivers carmustine directly into the surgical cavity created after tumoural resection. On exposure to the aqueous environment of the cavity the anhydride bonds in the copolymer are hydrolysed, releasing carmustine, carboxyphenoxypropane and sebacic acid. The carmustine released from GLIADEL Implant diffuses into the surrounding brain tissue and produces an antineoplastic effect by alkylating DNA and RNA. Carmustine is spontaneously both degraded and metabolised. The alkylating moiety thus produced and presumed to be chloroethyl carbonium ion, leads to the formation of irreversible DNA cross-links. The tumourcidal activity of GLIADEL Implant is dependent on release of carmustine into the tumour cavity in concentrations sufficient for effective cytotoxicity. More than 70% of the copolymer degrades by three weeks. The metabolic disposition and excretion of the monomers differ. Carboxyphenoxypropane is predominantly eliminated by the kidney and sebacic acid, an endogenous fatty acid, is metabolised by the liver and expired as CO2 in animals. Clinical data Primary surgery In a randomised, double-blind, placebo-controlled clinical trial in 240 adults with newly-diagnosed high grade malignant glioma undergoing initial craniotomy for tumour resection median survival increased from 11.6 months with placebo to 13.9 months with GLIADEL Implant (p-value 0.079, unstratified log-rank test) in the original study phase. The most common tumour type was Glioblastoma Multiforme (GBM) (n=207), followed by anaplastic oligoastrocytoma (n=11), anaplastic oligodendroglioma (n=11), and anaplastic astrocytoma (n=2). The hazard ratio for GLIADEL Implant was 0.77 (95% CI: 0.57 to 1.03). In the long term follow-up phase, patients still alive at the completion of the original phase were followed for up to at least three years or until death. Median survival increased from 11.6 months with placebo to 13.9 months with GLIADEL Implant (p-value <0.05, log-rank test). The hazard ratio for GLIADEL Implant treatment was 0.73 (95% CI: 0.56 to 0.95). Surgery for Recurrent Disease In a randomised, double-blind, placebo-controlled clinical trial in 145 adults with recurrent glioblastoma (GBM), GLIADEL Implant prolonged survival in these patients. Ninety-five percent of the patients treated with GLIADEL Implant received 7 to 8 implants. The six-month survival rate was 36% (26/73) with placebo compared to 56% (40/72) with GLIADEL Implant treatment. Median survival of GBM patients is 20 weeks with placebo versus 28 weeks with GLIADEL Implant treatment. 5.2 Pharmacokinetic properties The absorption, distribution, metabolism, and excretion of the copolymer in humans is unknown. Carmustine concentrations delivered by GLIADEL Implant in human brain tissue have not been determined. Plasma levels of carmustine after GLIADEL Implant implantation cannot be assayed. In rabbits that had implants containing 3.85% carmustine placed, carmustine is not detected in the blood or cerebrospinal fluid. Following an intravenous infusion of carmustine at doses ranging from 30 to 170mg/m2, the average terminal half-life, clearance, and steady-state volume of distribution are 22 minutes, 56mL/min/kg, and 3.25L/kg, respectively. Approximately 60% of the intravenous 200mg/m2 dose of 14C-carmustine is excreted in the urine over 96 hours and 6% is expired as CO2. GLIADEL Implants are biodegradable in human brain when placed into the cavity after tumour resection. The rate of biodegradation is variable from patient to patient. During the biodegradation process an implant remnant may be observed on brain imaging scans or at re-operation even though extensive degradation of all components has occurred. 5.3 Preclinical safety data No carcinogenicity, mutagenicity, embryo-foetal toxicity, pre- and post-natal toxicity and impairment of fertility studies have been conducted with GLIADEL Implants. Carmustine, the active component of GLIADEL Implant, when administered systemically, has embryotoxic, genotoxic and carcinogenic effects and can cause testicular degeneration in several animal models. 6. Pharmaceutical particulars 6.1 List of excipients Polifeprosan 20 6.2 Incompatibilities Not applicable.. 6.3 Shelf life 4 years 6.4 Special precautions for storage Store in a freezer at or below -20°C. Unopened outer sachets may be kept at a temperature of not more than 22°C for a maximum of six hours. The product may be refrozen only once if the sachets have been unopened and kept for a maximum of 6 hours at a temperature of not more than 22°C. After refreezing, the product should be used within 30 days. 6.5 Nature and contents of container GLIADEL Implant is available in a box containing eight implants. Each implant is individually packaged in two aluminium foil laminate sachets. 6.6 Special precautions for disposal and other handling Implants should be handled by personnel wearing surgical gloves because exposure to carmustine can cause severe burning and hyperpigmentation of the skin. Use of double gloves is recommended and the outer gloves should be discarded into a dedicated biohazard waste container after use. A surgical instrument dedicated to the handling of the implants should be used for implant placement. If repeat neurosurgical intervention is indicated, any implant or implant remnant should be handled as a potentially cytotoxic agent. Any unused product or waste material should be disposed of in accordance with local requirements. GLIADEL Implants should be handled with care. The sachets containing GLIADEL Implants should be delivered to the operating room and remain unopened until ready to place the implants in the resection cavity. Only the outside surface of the outer sachet is not sterile. In any case, if an implant is dropped, it should be discarded accordingly. Instructions for opening sachets containing the implant: • To open the outer sachet, locate the folded corner and slowly pull in an outward motion. Do not pull in a downward motion rolling knuckles over the sachet. This may exert pressure on the implant and cause it to break • Remove the inner sachet by grabbing with the aid of forceps and pulling upward • To open the inner sachet, gently hold it and cut in an arc-like fashion around the implant • To remove the implant, gently grasp the implant with the aid of forceps and place it directly into the resection cavity In any case, if an implant is dropped, it should be discarded accordingly. Once the tumour is resected, tumour pathology is confirmed and haemostasis is obtained, up to eight implants may be placed to cover as much of the resection cavity as possible. Slight overlapping of the implants is acceptable. Implants broken in half may be used, but implants broken in more than two pieces should be discarded in the dedicated biohazard waste containers. Oxidised regenerated cellulose may be placed over the implants to secure them to the cavity surface. After placement of the implants, the resection cavity should be irrigated and the dura closed in a water, tight fashion. Any unused product or waste material should be disposed of in accordance with local requirements for biohazardous waste. 7. Marketing authorisation holder MGI PHARMA LIMITED European Knowledge Centre Mosquito Way Hatfield Hertfordshire AL10 9SN United Kingdom 8. Marketing authorisation number(s) PL 18753/0001 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 28/05/1999 Date of last renewal: 10/12/2008 10. Date of revision of the text 02 February 2015 GLIADEL(CARMUSTINE)IMPLANT;INTRACRANIAL卡莫司汀植入膜剂-强推为治疗脑癌罕用药 Guilford制药公司日前宣布，其治疗脑癌的专利药：以聚苯丙生20为载体的卡莫司汀植入膜剂（polifeprosan 20 with carmustine implant，Gliadel）为罕用药，在治疗接受一期切除术的恶性胶质瘤患者领域享有的市场独占期。 本品为一种白色至灰白色的一角硬币大小的薄膜，包含生物可降解聚合物聚苯丙生20和7.7mg卡莫司汀（carmustine，BCNU），卡莫司汀是治疗恶性胶质瘤的常用静脉给药的化疗药物。当手术切除脑瘤时，在经手术创建的空腔中可最多植入8片本品。在植入处，本品将缓慢溶解，直接向肿瘤部位释放高浓度卡莫司汀，使扩散到其它部位的药物减至最少。 本品适应证是新诊断为高度恶性胶质瘤的患者的手术和放疗辅助药物，也可作为多形性胶质母细胞瘤（GBM）复发患者的手术辅助用药。 -------------------------------------------------------- 产地国家: 英国 原产地英文商品名: GLIADEL WAFER 7.7mg/Implant 8Implant/box 原产地英文药品名: Polifeprosan 20 with Carmustine Implant 中文参考商品译名: 格立得植入剂 7.7毫克/张 8张/盒 中文参考药品译名: 卡莫司汀 中文参考化合物名称: 可生物分解的聚酸酐192.3毫克及卡莫司汀7.7毫克 曾用名: 卡氮芥、氯乙亚硝脲、亚硝基脲芥 生产厂家中文参考译名: Eisai Ltd  生产厂家英文名: Eisai Ltd --------------------------------------------------- 产地国家: 美国 原产地英文商品名: GLIADEL WAFER 原产地英文药品名: Polifeprosan 20 with Carmustine Implant 原产地英文化合物名称: Carmustine 中文参考商品译名: 格立得植入剂 中文参考药品译名: 卡莫司汀植入膜剂 中文参考化合物名称: 可生物分解的聚酸酐192.3毫克及卡莫司汀7.7毫克 曾用名: 卡氮芥、氯乙亚硝脲、亚硝基脲芥 生产厂家中文参考译名: Eisai公司 生产厂家英文名: Eisai Corporation --------------------------------------------------- 产地国家: 日本 原产地英文商品名: GLIADEL WAFER（ギリアデル脳内留置用剤7）7.7mg/Implant 4-8Implant/box 原产地英文药品名: Carmustine 中文参考商品译名: 格立得植入剂（ギリアデル脳内留置用剤7）7.7毫克/张 4-8张/盒 中文参考药品译名: 卡莫司汀 中文参考化合物名称: 可生物分解的聚酸酐192.3毫克及卡莫司汀7.7毫克 曾用名: 卡氮芥、氯乙亚硝脲、亚硝基脲芥 生产厂家中文参考译名: Eisai Ltd 生产厂家英文名: Eisai Ltd http://www.info.pmda.go.jp/go/pack/4219700X1020_2_06/