2011年4月29日，Spectrum Pharmaceuticals公司宣布，美国食品药品管理局(FDA)已批准了Fusilev(左旋亚叶酸)的一项新适应证。该药现已获准与5-氟尿嘧啶联用，作为晚期转移性结直肠癌患者的姑息治疗。Fusilev是一种叶酸类似物，已获准的剂型包括即用的175 mg和250 mg两种瓶装注射液以及一种50 mg瓶装冻干粉剂。 除了结直肠癌外，Fusilev还可用作骨肉瘤患者行高剂量甲氨蝶呤治疗后的补救治疗药。此外，Fusilev的适应证还包括减轻化疗药物的毒性，对抗甲氨蝶呤消除受损和叶酸拮抗剂意外过量所产生的不良影响。 据Spectrum Pharmaceuticals公司的发言人称，美国国家综合癌症网(NCCN)结直肠癌治疗指南已经推荐将左旋亚叶酸用于治疗结直肠癌。 晚期结直肠癌患者在采用Fusilev联合5-氟尿嘧啶治疗方案后最常发生的不良反应为腹泻、恶心和胃炎。Fusilev可以与抗癫痫药发生相互作用，其中包括苯巴比妥、苯妥英以及普里米酮，并可增加疑似患者的癫痫发作频率。 Fusilev禁用于既往曾发生叶酸或亚叶酸过敏反应的患者。由于其含有钙，故每分钟静脉输注的左旋亚叶酸注射液量不得超过16ml(160mg)。 Fusilev®（levoleucovorin）FOR针剂，粉针剂，冻干，为解决方案用于静脉使用 Fusilev®（levoleucovorin）注射剂，溶液静脉使用 初始的美国批准：1952（D，L-亚叶酸），2008（levoleucovorin） 目前的主要变化 适应证和用途04/2011 用法与用量，Fusilev总局联合5-氟尿嘧啶  04/2011 剂量和给药方法，重组和输液说明  04/2011 作用机理 大剂量甲氨蝶呤治疗期间1.1 Levoleucovorin影响 Levoleucovorin是5-甲酰四氢叶酸的药理活性异构体。 Levoleucovorin不需要被酶二氢叶酸还原酶的还原，以参加利用叶酸作为“一碳”部分的源的反应。 levoleucovorin的施用可以抵消叶酸拮抗剂例如甲氨蝶呤，通过抑制二氢叶酸还原酶作用的治疗性和毒性作用。 Levoleucovorin效果结合5-氟尿嘧啶 Levoleucovorin可以增强在癌症治疗中，如5-氟尿嘧啶用于氟尿嘧啶治疗性和毒性作用。 5-氟尿嘧啶代谢成5-氟-2'-脱氧尿苷-5'-一磷酸（FdUMP），其结合并抑制胸苷酸合成酶（酶在DNA修复和复制重要）。 Levoleucovorin很容易转化为另一种还原叶酸，5,10-亚甲基四氢叶酸，其作用是稳定FdUMP的结合胸苷酸合成酶，从而增强了这种酶的抑制。 适应症和用法 Fusilev是叶酸的模拟显示为： 在骨肉瘤大剂量甲氨蝶呤治疗后抢救。 减少毒性和抵制叶酸拮抗剂过量不慎甲氨蝶呤消除损害和影响。 在姑息性治疗的晚期转移性结直肠癌患者使用联合化疗与5-氟尿嘧啶。 使用限制 Fusilev没有批准用于恶性贫血和巨幼红细胞性贫血。使用不当可能会导致血液学缓解，而神经系统表现不断进步。 用法用量 不要鞘内给药。 Fusilev在二分之一的外消旋的d，l-亚叶酸的常用剂量给药。 Fusilev救援大剂量甲氨蝶呤治疗后 Fusilev救援建议基于的通过静脉输注在4小时内给药12克/m 2的氨甲喋呤剂量。在对10个剂量的剂量为7.5毫克（约5毫克/米2），每6小时Fusilev救援甲氨蝶呤输注的开始24小时后开始。每天至少一次测定血清肌酐和甲氨蝶呤水平。继续Fusilev施用，水化和尿碱化（7.0或更高pH值），直到甲氨蝶呤水平低于5×10-8M（0.05微摩尔）。所述Fusilev剂量可能需要调整。 与5-氟尿嘧啶组合Fusilev管理局（5-FU） 下面的方案已经被历史用于结直肠癌的治疗方法： Fusilev在100毫克/通过缓慢静脉注射在最少3分钟平方米施用，接着用5-FU在通过静脉内注射370毫克/米2。 Fusilev通过静脉内注射，接着用5-FU在通过静脉内注射425毫克/米210毫克/米2施用。 5-FU和Fusilev应单独施用，以避免沉淀物的形成。 治疗每天重复五天。这五天疗程可在4周（28天）的时间间隔被重复，2个疗程，然后于4重复至5周（28〜35天）的间隔设置，该患者已完全从的毒性作用回收以前的治疗过程。 在后续的疗程，5-FU的剂量应根据现有疗程的患者耐受调节。5-FU的日剂量应该由20％谁经历在现有治疗过程中等血液学或胃肠道毒性，和30％为谁经历了严重的毒性患者的患者被减少。对于谁经历在现有疗程没有毒性的患者，5-FU剂量可以由10％增加。 Fusilev剂量未调整的毒性。 剂型和规格 Fusilev注射：Fusilev的每50毫克单次使用的小瓶含有由64毫克levoleucovorin钙五水合物（相当于50毫克levoleucovorin）和50mg甘露糖醇的无菌冻干粉末。其目的是为5.3毫升无菌的0.9％氯化钠注射液，USP复原后静脉内给药。 Fusilev注射：17.5毫升含levoleucovorin钙五水合物相当于175毫克levoleucovorin和0.83％氯化钠的无菌溶液。 Fusilev注射：25毫升含levoleucovorin钙五水合物相当于250毫克levoleucovorin和0.83％氯化钠的无菌溶液。 禁忌症 Fusilev是禁忌谁曾归因于叶酸或亚叶酸以前过敏反应的患者。 警告和注意事项 由于钙++含量，levoleucovorin解不超过16毫升（160毫克），应每分钟静脉注射。 Fusilev增强氟尿嘧啶的毒性。 同时使用的D，L-亚叶酸与复方新诺明对艾滋病患者卡氏肺囊虫肺炎是在一个安慰剂对照研究治疗失败率增加有关。 不良反应 过敏反应的报道在接受Fusilev病人。 呕吐（38％），口腔炎（38％）和恶心（19％）的报道对收到Fusilev高剂量甲氨蝶呤治疗后抢救的患者。 最常见的不良反应（> 50％）患者晚期大肠癌接收Fusilev联合5-FU为腹泻，恶心，口腔炎。 药物相互作用 Fusilev可能抵消苯巴比妥，苯妥英和扑米酮的抗癫痫作用，并增加在易感患者发作的频率。 FDA, in 2008. It is indicated as a side treatment in the patients suffering from cancer. Those with bone cancer are usually treated with methotrexate. Most cancer drugs are harmful enough and leave major marks on the patients, but this one is above the limits. It is almost imperative for the specialist doctor to prescribe a medicine to deal with the side effects. The active substance levoleucovorin seems to be the most appropriate solution. Aside from the general side effects, the patients may also end up with a methotrexate retention, as well as an overdose. Fusilev (levoleucovorin) is indicated in all these situations. It may be taken with a medical prescription, after the patient is initially evaluated. It cannot treat other problems or issues. Administration Fusilev (levoleucovorin) is administered intravenously, through an IV line. Unlike other injections, this one can only be administered in a clinic or a hospital. This way, the specialist doctor can constantly monitor you, while the side effects can be treated as soon as they arise, if they do. Besides, the overdose risks are eliminated since the drug is given by a professional. The drug must be administered very slowly. The infusion can take up to 4 hours. The frequency of these infusions also indicate the hospital. You will most likely have to be retained in the hospital for the duration of the treatment. Such long infusions are taken at every 6 hours. You need 10 of them. Therefore, your free time is quite limited. The frequency and duration of the treatment may differ, according to your condition. The treatment should begin one day after you start the methotrexate therapy. In case of an overdose, it should be started within one day. When treating the drug retention, it must be started as soon as the problem is diagnosed. During the Fusilev (levoleucovorin) treatment, your blood requires continuous monitoring. Warnings The levoleucovorin allergic patients are supposed to get a different treatment for their condition. Such tests should be performed before initializing the treatment. Tell the doctor if you suffer from any renal or hepatic dysfunctions or dehydration. You might need a smaller dose. The effects of Fusilev (levoleucovorin) are not known in pregnant or nursing women, so they must be careful. Adverse reactions Some of the adverse reactions you might experience consist of fever, nausea, diarrhea, rash or stomach upset. They should be mild or moderate. Indications and Usage FUSILEV is a folate analog indicated for: Rescue after high-dose methotrexate therapy in osteosarcoma. Diminishing the toxicity and counteracting the effects of impaired methotrexate elimination and of inadvertent overdosage of folic acid antagonists. Use in combination chemotherapy with 5-FU in the palliative treatment of patients with advanced metastatic colorectal cancer. Limitations of Use FUSILEV is not approved for pernicious anemia and megaloblastic anemias. Improper use may cause a hematologic remission while neurologic manifestations continue to progress. Important Safety Information Contraindications FUSILEV is contraindicated for patients who have had previous allergic reactions attributed to folic acid or folinic acid. Warnings and Precautions Due to Ca++ content, no more than 16 mL (160 mg) of levoleucovorin solution should be injected intravenously per minute. FUSILEV enhances the toxicity of fluorouracil. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly d,l-leucovorin and 5-fluorouracil. When these drugs are administered concurrently in the palliative treatment of advanced colorectal cancer, the dosage of 5-FU must be lower than usually administered. Although the toxicities observed in patients treated with the combination of FUSILEV and 5-FU are qualitatively similar to those observed with 5-FU alone, gastrointestinal toxicities (particularly stomatitis and diarrhea) are observed more commonly and may be of greater severity and of prolonged duration in patients treated with the combination. Concomitant use of d,l-leucovorin with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia in HIV patients was associated with increased rates of treatment failure in a placebo-controlled study. Adverse Reactions Allergic reactions were reported in patients receiving FUSILEV. The most common adverse reactions (>50%) in patients with advanced colorectal cancer receiving FUSILEV in combination with 5-FU were diarrhea, nausea and stomatitis. Vomiting (38%), stomatitis (38%) and nausea (19%) were reported in patients receiving FUSILEV as rescue after high dose methotrexate therapy. Drug Interactions FUSILEV may counteract the antiepileptic effect of phenobarbital, phenytoin and primidone, and increase the frequency of seizures in susceptible patients. FUSILEV adverse event profile Adverse reactions (≥10% in either arm) in patients with advanced metastatic colorectal cancer Adverse Reaction Levoleucovorin/5FU n=318 d,l-Leucovorin/5FU n=307 Adverse Event N (%) Grade 1–4 Grade 3–4 Grade 1–4 Grade 3–4 Gastrointestinal Disorders Stomatitis 229 (72%) 37 (12%) 221 (72%) 44 (14%) Diarrhea 222 (70%) 61 (19%) 201 (65%) 51 (17%) Nausea 197 (62%) 25 (8%) 186 (61%) 26 (8%) Vomiting 128 (40%) 17 (5%) 114 (37%) 18 (6%) Abdominal Pain* 45 (14%) 10 (3%) 57 (19%) 10 (3%) General Disorders Asthenia/Fatigue/Malaise 91 (29%) 15 (5%) 99 (32%) 34 (11%) Metabolism and Nutrition Anorexia/Decreased Appetite 76 (24%) 13 (4%) 77 (25%) 5 (2%) Skin Disorders Dermatitis 91 (29%) 3 (1%) 86 (28%) 4 (1%) Alopecia 83 (26%) 1 (0.3%) 87 (28%) 3 (1%) Includes abdominal pain, upper abdominal pain, lower abdominal pain, and abdominal tenderness ISI-0154-079600 --------------------------------------------------------------- 产地国家: 美国 原产地英文商品名: FUSILEV I.V. 50mg/10ml/vial 原产地英文药品名: LEVOLEUCOVORIN CALCIUM 中文参考商品译名: FUSILEV I.V. 50毫克/10毫升/瓶 中文参考药品译名: 左旋亚叶酸钙 生产厂家中文参考译名: SPECTRUM PHARMS 生产厂家英文名: SPECTRUM PHARMS -------------------------------------------------------- 产地国家： 美国  原产地英文商品名: FUSILEV Injection solution 175mg/17.5ml(10mg/ml)/vial 原产地英文药品名: Levoleucovorin calcium 中文参考商品译名: FUSILEV注射溶液 175毫克/17.5毫升(10毫克/毫升)/瓶 中文参考药品译名: 左旋亚叶酸钙 生产厂家中文参考译名: Spectrum Pharmaceuticals, Inc 生产厂家英文名: Spectrum Pharmaceuticals, Inc -------------------------------------------------------- 产地国家： 美国  原产地英文商品名: FUSILEV   Injection solution 250mg/25ml(10mg/ml)/vial  原产地英文药品名: Levoleucovorin calcium 中文参考商品译名: FUSILE注射溶液 250毫克/25毫升(10毫克/毫升)/瓶 中文参考药品译名: 左旋亚叶酸钙 生产厂家中文参考译名: Spectrum Pharmaceuticals, Inc 生产厂家英文名: Spectrum Pharmaceuticals, Inc