英文药名：Removab(catumaxomab solution infusion) 中文药名：卡妥索单抗输液 生产厂家：费森尤斯公司 药品介绍 欧盟委员会扩大了费森尤斯生物技术部门研发的抗体Removab的应用范围。该抗体现可用于缩短恶性腹水患者的输液时间。 输液时间可以因此缩短一半，从6小时缩减至3小时。此外研究结果显示，该抗体也可用于治疗恶性腹水疾病。这样，使用Removab的患者一年的存活率比采用保守治疗的患者要高四倍。经欧洲药品管理局人用医疗产品委员会的推荐，该三功能抗体的安全性被证实并获得许可。该许可在所有欧盟国家适用。 用法与用量 本品经由腹腔输注。使用前需以50mL 0.9％氯化钠溶液稀释，再通过恒速输液泵腹腔内给药。 本品推荐的给药方案为： 第1剂：剂量为10mg，给药时间为“第0天”； 第2剂：剂量为20mg，给药时间为“第3天”； 第3剂：剂量为50mg，给药时间为“第7天”； 第4剂：剂量为100mg，给药时间为“第10天”。 给药间隔至少2天，可视不良反应情况适当延长。总治疗时间不超过20天。 制剂 本品为预填充注射剂，有两种规格，每支注射器分别装入0.1mL(10μg)溶液 和0.5 mL(50μg)溶液。 --------------------------------------------- 产地国家：德国  原产地英文商品名: Removab 10ug/SYRINGE 原产地英文药品名: atumaxomab  中文参考商品译名: Removab预填充注射剂 10微克/注射器  中文参考药品译名: 卡妥索单抗 生产厂家中文参考译名: Fresenius Biotech Gmbh 生产厂家英文名: Fresenius Biotech Gmbh --------------------------------------------- 产地国家：德国  原产地英文商品名: Removab 50ug/SYRINGE 原产地英文药品名: atumaxomab  中文参考商品译名: Removab预填充注射剂 50微克/注射器  中文参考药品译名: 卡妥索单抗 生产厂家中文参考译名: Fresenius Biotech Gmbh 生产厂家英文名: Fresenius Biotech Gmbh catumaxomab (Removab®) Appraisal information catumaxomab (Removab®) 10 micrograms concentrate for solution for infusion catumaxomab (Removab®) 50 micrograms concentrate for solution for infusion Removab (catumaxomab) is now available to treat malignant ascites due to EpCAM-positive carcinomas where standard therapy is not available or not feasible. Catumaxomab is a hybrid rat-mouse monoclonal antibody that has binding sites for the epithelial cell adhesion molecule (EpCAM) and CD3, a component of the T cell receptor. It stimulates a range of immune responses against tumour cells. A randomised, open-label trial compared catumaxomab (as 4 intraperitoneal infusions) plus paracentesis with paracentesis alone in 258 patients with symptomatic malignant ascites due to EpCAM-positive carcinomas. Median puncture-free survival, the primary endpoint, was significantly longer with catumaxomab than with drainage alone (46 days vs 11 days; p<0.0001). Median time to the next therapeutic puncture was also significantly increased in the catumaxomab group compared with the drainage-alone group (77 days versus 13 days; p<0.0001) and there was a trend towards increased overall survival with catumaxomab (72 days vs 68 days; p=0.0846). ---------------------------------------------------- Removab  concentrate for solution for infusion What is it and how is it used? Removab contains the active substance catumaxomab, a monoclonal antibody. It recognises a protein on the surface of cancer cells and recruits immune cells to destroy them. Removab is used to treat malignant ascites,when standard treatment is not available or no longer feasible. Malignant ascites is an accumulation of fluid in the abdominal space (peritoneal cavity) resulting from certain types of cancer. What do you have to consider before using it? Do not use Removab if you are allergic (hypersensitive) to catumaxomab or any of the other ingredients of Removab (see section 6) if you are allergic (hypersensitive) to murine proteins (from rat and / or mouse) Take special care with Removab It is important to tell your doctorif you have any of the following: undrained fluid in your abdominal cavity cold hands and feet, light headedness, difficulty passing urine, increased heart rate, and weakness (symptoms of low blood volume) weight gain, weakness, shortness of breath and fluid retention (symptoms of low blood protein levels) feeling dizzy and faint (symptoms of low blood pressure) problems with your heart and circulation kidney or liver problems an infection. Removab should not be used in children and adolescents under 18 years of age. Before you start using Removab your doctor will check your: Body Mass Index (BMI), which depends on your height and weight Karnofsky Index, a measure of your general performance status. You are required to have a BMI above 17 (after drainage of the ascites fluid) and a Karnofsky Index above 60 to use this medicine. Taking other medicines Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines including those obtained without a prescription. Pregnancy and breast-feeding You should not use Removab if you are pregnant unless clearly necessary. Talk to your doctor if you are, might be or are planning to become pregnant. If you are breast-feeding, talk to your doctor before starting treatment. Driving and using machines There are no studies on the effects of Removab on the ability to drive and use machines.However, if you experience side effects such as dizziness or chills during or after administration, you should not drive or use machines until they disappear. How is it used? You will be given Removab under the supervision of a doctor experienced in treating cancer. After the Removab infusion you will be observed as decided by your doctor. Before starting and during treatment, you will be given other medicines to reduce fever, pain or inflammation caused by Removab. A catheter will be placed in your abdominal space (intraperitoneal) for the whole treatment period, until the day after your last infusion. Removab is given as 4 intraperitoneal infusions with increasing dose (10, 20, 50 and 150 micrograms), separated at least by a 2-day break. If you have any further questions on the use of this product, ask your doctor. What are possible side effects? Like all medicines, Removab can cause side effects, although not everybody gets them. These side effects may occur with certain frequencies, which are defined as follows: very common: affects more than 1 user in 10 common: affects 1 to 10 users in 100 uncommon: affects 1 to 10 users in 1,000 rare: affects 1 to 10 users in 10,000 very rare: affects less than 1 user in 10,000 not known: frequency cannot be estimated from the available data. Serious side effects Some of these side effects may be serious and require medical treatment. You should tell a doctor immediately if you experience any of these serious side effects. Very common serious side effects: Abdominal pain Fever Common serious side effects: Abdominal pain accompanied by difficulty passing stools Shortness of breath Uncommon serious side effects: Very fast heart beat, fever, shortness of breath, feeling faint or light-headed within 24 hours of infusion. Blockage in the gut or bowel Bleeding in the stomach, shown by the vomiting of blood or the passage of red or black stools Inflammation and pain or burning and stinging in the area around the catheter Infection of the skin Fits Lung problems including blood clot in the lungs or accumulation of fluid around the lungs which cause chest pain and breathlessness Severe skin reactions such as flaking of the skin, rash and sensitive skin Severe kidney problems Other side effects Very common side effects: Feeling sick (nausea), vomiting and diarrhoea Tiredness, pain and chills Reduction in number of white blood cells Common side effects: Increased number of white blood cells Increased clotting factors Reduction in red blood cells (anaemia) Decreased blood levels of calcium, potassium and sodium Decreased blood protein levels High blood sugar A very fast heart beat Spinning sensation Constipation, indigestion, stomach problems, heartburn, passing wind and mouth ulcers Flu-like symptoms Fluid retention Dizzinessor headache Chest pain Increased sweating, feeling thirsty and weak Liver problems and yellowing of the skin (jaundice) Infectionsincluding bladder infections Lumps under the skin on the back of the legs that may become sores and leave scars Increased protein levels or white blood cells in urine Loss of appetite Dehydration Back pain, aching muscles and joints Feeling anxious and having difficulty sleeping. Passing small amounts of urine or finding blood in the urine Skin redness, itchy rash, hives, sensitive skin or a sudden widespread rash High or low blood pressure Flushing and hot flushes. If any of the side effects become serious or if you notice any side effects not listed in this leaflet, tell your doctor or nurse. How should it be stored? Keep out of the reach and sight of children. Do not use Removab after the expiry date which is stated on the carton after EXP. The expiry date refers to the last day of that month. Store in a refrigerator (2°C – 8°C). Do not freeze. Store in the original package in order to protect from light. http://europepmc.org/articles/PMC2840231 临床研究终点证实：removab(R)抗体治疗恶性腹水疗效显着 根据美国商业新闻社 (Business Wire)报导，费森尤斯公司(Fresenius)今天宣布，针对恶性腹水患者进行的removab(R)(catumaxomab)二、三期临床试验次要终点的详细资料证实，这种抗体能为患者带来显着疗效。 试验资料显示，removab能明显推後肿瘤出现进展的时间，并对总体存活时间产生积极的影响。 此外，与对照组相比，施用removab的小组的必要穿刺术时间间隔延长了；在研究结束之後，仍可观察到这一效应。 这项随机临床研究的结果包含了258名恶性腹水患者的治疗资料；恶性腹水的病因源自各类癌症。大部分患者已处於疾病晚期，平均预期寿命为两到三个月。该项临床研究的主要终点显示，与单一的穿刺治疗相比，接受removab治疗的患者，其免穿刺存活期提高了四倍(前者的免穿刺存活期为11天，後者则为46天，p<0.0001)。作为关键的次要终点指标，removab组接受第一次穿刺治疗的中位数时间间隔提高到77天，而对照组则为13天(p<0.0001)。与主要终点不同，下一次穿刺之前死亡的患者资料不记入指标。 两组研究物件体内的癌症进展时间(TTP)差别显着。采用removab进行治疗的170名患者，其中位数的进展时间(次要终点)为111天，与此相比，对照组的88名患者则为35天(p<0. 0001)。在卵巢癌致病的腹水患者小分组，采用removab治疗的患者，其中位数的进展时间也是111天，与此相比，对照组患者则为35天(p=0.0002)。此外，其他常见癌症的患者接受removab治疗时，疾病出现进展的时间也显着延长，其中位数值为110天，而采用单一的穿刺疗法的患者则为34天(p<0.0001)。 从总体存活期来看，趋势也较为乐观。Removab组170名患者的中位数总体存活期为72天，而对照组的88名患者则为68天(p=0.0846)。每套临床试验方案治疗131名患者；对这些患者进行预先规划的评估时，发现存在18天的中位数存活期优势(removab组：86天，对照组则为：68天，p=0.0085)。结果还显示，removab疗法对延长卵巢癌患者的总体存活期有积极的影响，采用这种疗法，中位数存活期为110天，而接受单一穿刺治疗的患者，其中位数存活期则为81天(p=0.1543)。采用removab疗法，胃癌患者(卵巢癌患者之外最大的癌症患者小分组)的中位数存活期能多延长27天(71天对44天，p=0.0313)。 资料显示，达到临床试验主要终点(免穿刺存活期)後，采用removab治疗的患者，其穿刺治疗的时间间隔仍比对照组的患者要长。卵巢癌和非卵巢癌患者组采用removab治疗，初次和第二次穿刺治疗的间隔分别为26天和24天；而对照组的间隔分别为13天和16天。 次要研究终点，以及达到主要终点後收集的其他患者资料证实了removab治疗晚期患者组的疗效。总体来说，这些研究结果再次展示了removab治疗各类常见癌症的功效。 费森尤斯生物技术公司(FreseniusBiotech)总裁Bernhard Ehmer博士说，「二、三期临床研究的结果显示，removab具有明显的疗效。这些结果还显示了这种三功能抗体的直接抗癌效应。主要终点、次要终点和研究结束後的资料是一致的，突出显示了乐观的发展趋势。这些都说明，我们的研究方向是正确的。因此，我们有信心继续开发卵巢癌和胃癌治疗计画。」 费森尤斯生物技术公司证实，预计於2007年年末向欧洲药品评价局(EMEA)提交销售许可申请。 关於removab二、三期临床研究 共有258名患者参加了此次临床研究，他们都患有晚期癌症，伴有复发性恶性腹水症状，对他们来说，化疗要麽已经不再有效，要麽就是患者本人无法再接受化疗。129名患者患有卵巢癌，并有129名患者患有其他形式的上皮肿瘤(胃癌占51%，乳腺癌占10%，胰腺癌占7%，直肠癌占6%，其他癌症占26%)。参与临床试验的患者以2：1的比例随机分组，其中170名患者接受removab治疗，88名患者只接受穿刺治疗。达到研究的终点之後，也向51%的对照组患者提供removab(交叉对照)。施行穿刺手术後，在0，3，7，10日，向腹膜内注射removab，剂量逐渐加大。131名患者四次分别注射10微克、20微克、50微克、150微克。 三功能抗体removab(catumaxomab)的作用方式 三功能抗体的治疗目标是，针对肿瘤细胞产生更强的免疫反应。removab有两处不同的抗原结合点：抗体的一支手臂识别并结合T细胞，另一支与多种上皮癌症中过度表达的EpCAM(上皮细胞粘附分子)结合。具有Fc受体的免疫效应细胞(巨噬细胞、单核细胞、树突细胞、自然杀伤细胞)也能与完整三功能抗体的Fc段相结合。同步结合随後造成T细胞和佐细胞的共刺激，并使之启动，从而针对肿瘤细胞生成强烈的免疫反应。临床前资料也显示，该疗法有预防癌症复发的长效潜力。除了removab，另有两种针对其他癌症抗原的三功能抗体正在进行临床开发。 三功能抗体 三功能抗体属於蛋白质，能够同时启动免疫系统不同类型的细胞，并针对具体肿瘤细胞产生作用。因此，三功能抗体能够非常有效地杀灭癌细胞，即使小剂量施用时也能产生治疗效果。TRION Pharma GmbH正在开发这些抗体。 费森尤斯生物技术公司隶属费森尤斯医疗集团，面向肿瘤学、免疫学和再生医学领域，致力於生物药品的开发和销售。 费森尤斯医疗保健集团开展全球业务，为透析、医院和门诊医疗护理提供产品和服务。集团2006年的销售额接近108亿欧元。截止到2007年3月31日，费森尤斯集团全球员工总数达到107348人。 Trion Pharma公司是慕尼克的一家生物制药企业，与费森尤斯生物技术公司合作，利用全球专利技术平台，开发、生产三功能抗体。 免穿刺存活期(Puncture-free survival period)：上一次注射之日起(对於对照组来说，指穿刺手术的日期)，直到患者必须施行穿刺治疗之日或死亡之日(以先发生者为准)的时间间隔。 进展时间(TTP，Time to Progression)：进展时间是指从治疗日期开始，到主要肿瘤或转移状况再次恶化的时间长度。