MEKINIST(trametinib)片于2013年获美国FDA批准为治疗有不可切除的(不能用外科去除)和转移(晚期)晚期黑色素瘤患者的口服使用 作用机制 Trametinib是丝裂原活化的细胞外信号调节激酶1(MEK1)和MEK2激活和MEK1和MEK2激酶活性的可逆性抑制剂。MEK蛋白质是细胞外信号相关激酶(ERK)通路的上游调节器，它促进细胞增殖。BRAF V600E突变导致BRAF通路的组成性激活，其中包括MEK1和MEK2。Trametinib在体外和体外抑制BRAF V600突变-阳性黑色素瘤细胞生长。 Trametinib和dabrafenib靶向RAS/RAF/MEK/ERK通路中两个不同的酪氨酸激酶。Trametinib和dabrafenib的联合使用与任一药物单独使用比较导致BRAF V600突变-阳性黑色素瘤细胞株在体外更大抑制作用和在BRAF V600突变阳性黑色素瘤异种移植物肿瘤生长延长的抑制作用。 适应证和用途 MEKINIST是一种激酶抑制剂适用作为单药和与dabrafenib联用为通过一种FDA-批准的检验检出有BRAF V600E和V600K突变的不可切除的或转移黑色素瘤患者的治疗。联合的使用是根据持久反应率的显示。尚未证实对MEKINIST与dabrafenib联用疾病相关的症状和总体生存的改善。 使用的限制：MEKINIST作为单药不适用为曾接受既往BRAF-抑制剂治疗患者的治疗。 剂量和给药方法 （1）开始用MEKINIST治疗前确认在肿瘤样品中存在BRAF V600E和V600K突变。 （2）MEKINIST的推荐剂量方案是2mg口服每天1次作为单药和与dabrafenib 150 mg联用口服每天2次。餐前至少1小时和餐后至少2小时服用MEKINIST。 剂型和规格 片：0.5mg，1mg，和2mg。 禁忌证 无。 警告和注意事项 （1）新原发恶性病，皮肤和非皮肤：当MEKINIST被使用与dabrafenib联用可能发生。治疗开始前和用治疗，和联合治疗终止后监视患者新恶性病。 （2）出血：接受MEKINIST与dabrafenib联用患者可能发生重大出血事件。监视出血体征和症状。 （3）静脉血栓栓塞：接受MEKINIST与dabrafenib联用患者可能发生深静脉血栓形成和肺栓塞。 （4）心肌病：治疗前，治疗后1个月，其后然后每2至3个月评估LVEF。 （5）眼毒性：对任何视力障碍进行眼科评价。 对视网膜静脉阻塞(RVO)，永久终止MEKINIST （6）间质性肺疾病(ILD)：对新和进展性不能解释的肺症状不给MEKINIST。对治疗-相关ILD和肺炎永久终止MEKINIST。 （7）严重发热反应：当MEKINIST被使用与dabrafenib联用时可能发生。 （8）严重皮肤毒性：监视皮肤毒性和继发感染。对不可耐受的2级，和3和4级皮疹尽管中断MEKINIST 3周内不改善终止用药。 （9）高血糖：在预先存在糖尿病和高血糖患者监视血清糖水平。 （10）胚胎胎儿毒性：可能致胎儿危害. 忠告有生殖潜能女性对胎儿风险。 不良反应 （1）最对MEKINIST作为单药常见不良反应(≥20%)包括皮疹，腹泻，和淋巴水肿. （2）为MEKINIST用dabrafenib联用最常见不良反应(≥20%)包括发热，畏寒，疲乏，皮疹，恶心，呕吐，腹泻，腹痛，外周性水肿，咳嗽，头痛，关节痛，夜汗，食欲减低，便秘，和肌痛。 药物相互作用 （1）当MEKINIST被使用与dabrafenib联用时避免同时给予CYP3A4和CYP2C8的强抑制剂。 （2）当MEKINIST被使用与dabrafenib联用时避免同时给予CYP3A4和CYP2C8强诱导剂。 （3）当MEKINIST被使用与dabrafenib联用时同时使用药物是CYP3A4，CYP2C8，CYP2C9，CYP2C19,和CYP2B6敏感底物，导致这些药物丧失疗效。 特殊人群中使用 （1）哺乳母亲：终止药物和哺乳。 （2）有生殖潜能女性和男性：与女性患者商议妊娠计划和预防。可能损伤生育能力。 MEKINIST® Class: Biological Therapy Generic Name:Trametinib Trade Name:MEKINIST® For which conditions is this drug approved? MEKINIST is indicated for the treatment of patients with unresectable (unable to be removed with surgery) or metastatic melanoma with a specific type of BRAF mutation (BRAF V600E or V600K), as detected by an FDA-approved test. What is the mechanism of action? MEKINIST is a kinase inhibitor. These drugs work by blocking the action of enzymes called kinases, which are involved in many cell functions, including cell signaling, growth, and division. These enzymes may be too active or found at high levels in some types of cancer cells and blocking them may help keep cancer cells from growing. Specifically, MEKINIST targets kinases called mitogen-activated extracellular signal-regulated kinase 1 and 2 (MEK1 and MEK2), which are involved in cell growth in metastatic melanoma with BRAF V600E or V600K mutations. How is MEKINIST typically given (administered)?MEKINIST is approved to be given as a single agent and in combination with the drug TAFINLAR® (dabrafenib), also a kinase inhibitor. As a single agent, the recommended dosage of MEKINIST is 2 mg orally once daily. In combination with TAFINLAR, the recommended dosage is 150 mg orally twice daily. Take MEKINIST at least 1 hour before or at least 2 hours after a meal. How are patients typically monitored? Because MEKINIST can cause new or worsening high blood pressure (hypertension), your healthcare provider should check your blood pressure regularly during treatment with MEKINIST. Some people may develop high blood sugar or worsening diabetes during treatment with MEKINIST in combination with TAFINLAR. If you are diabetic and receiving MEKINIST plus TAFINLAR, your healthcare provider should check your blood sugar levels closely during treatment. What are the common (occur in 20% or more of patients) side effects of treatment with MEKINIST as a single agent? Rash Diarrhea Lymphedema What are the common (occur in 20% or more of patients) side effects of treatment with MEKINISTin combination with TAFINLAR? Fever Chills Fatigue Rash Nausea Vomiting Diarrhea Abdominal pain Peripheral edema Cough Headache Joint pain Night sweats Decreased appetite Constipation Pain in a muscle or group of muscles This is not a complete list of side effects. Some patients may experience other side effects that are not listed here. Patients may wish to discuss with their physician the other less common side effects of this drug, some of which may be serious. Some side effects may require medical attention. Other side effects do not require medical attention and may go away during treatment. Patients should check with their physician about any side effects that continue or are bothersome. What can patients do to help alleviate or prevent discomfort and side effects? Tell your doctor if you have or have had any medical condition, with special attention to the following: Bleeding problems or blood clots Heart problems Eye problems Lung or breathing problems High blood pressure (hypertension) Liver or kidney problems Also tell your doctor is you are pregnant or plan to become pregnant. MEKINIST can harm your unborn baby, and women who are able to become pregnant should use effective birth control during treatment and for four months after stopping treatment. If you’re taking MEKINIST with TAFINLAR, be aware that birth control using hormones (such as birth control pills, injections, or patches) may not work as well with this combination, so use another effective method of birth control. Tell you doctor if you are breastfeeding or plan to breastfeed; it is not known if MEKINIST passes into your breast milk, so you should not take this drug while breastfeeding. Take MEKINIST one time a day exactly as your healthcare provider tells you to take it. Do not change your dose or stop MEKINIST unless your healthcare provider tells you. If you miss a dose, take it as soon as you remember. If it is within 12 hours of your next scheduled dose, skip the missed dose and take the next dose at your regular time. If you take too much MEKINIST, call your healthcare provider or go to the nearest hospital emergency room right away. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Are there any special precautions patients should be aware of before starting treatment? Because MEKINIST can cause fetal harm if taken during pregnancy, female patients should use highly effective contraception during treatment and for four months after treatment. Patients take MEKINIST in combination with TAFINLAR should use a highly effective non-hormonal method of contraception. If you do become pregnant during treatment with MEKINIST, contact your healthcare provider immediately. When should patients notify their physician? Tell your doctor if you experience any side effects that bother you or don’t go away. Also call your healthcare provider right away if: You develop high blood pressure, your blood pressure worsens, or you have severe headache, lightheadedness, or dizziness. You have symptoms of severe high blood sugar, such as increased thirst urinating more often than normal, or urinating an increased amount of urine. You have symptoms of a heart problem, including feeling like your heart is pounding or racing, shortness of breath, swelling of your ankles and feet, or feeling lightheaded. You have signs of a blood clot, including chest pain, sudden shortness of breath or trouble breathing, pain in your legs with or without swelling, swelling in your arms or legs, a cool or pale arm or leg You have unusual signs of bleeding, such as: headaches or dizziness; if you feel weak, cough up blood or blood clots, vomit blood; your vomit looks like coffee grounds; or your stools red or black stools and look like tar You any new lesions, changes to existing lesions on their skin, or other signs and symptoms of malignancies You develop rash or fever What is a package insert? A package insert is required by the FDA and contains a summary of the essential scientific information needed for the safe and effective use of the drug for healthcare providers and consumers.  A package insert typically includes information regarding specific indications, administration schedules, dosing, side effects, contraindications, results from some clinical trials, chemical structure, pharmacokinetics and metabolism of the specific drug. By carefully reviewing the package insert, you will get the most complete and current information about how to safely use this drug. If you do not have the package insert for the drug you are using, your pharmacist or physician may be able to provide you with a copy. 美国FDA批准GSK旗下药物mekinist和tafinlar作为黑色素瘤新组合疗法上市 2014年1月10日,美国食品药品监督管理局(FDA)批准Mekinist(trametinib)与Tafinlar (dabrafenib)联用治疗有不可切除的(不能用外科去除)和转移(晚期)晚期黑色素瘤患者。 2013年5月，FDA批准两药作为单药治疗不可切除的或转移黑色素瘤患者。黑色素瘤是最具侵略性类型皮肤癌和是来自皮肤疾病主要死亡病因。美国国家癌症研究所估计2013年76,690美国人将被诊断有黑色素瘤和9,480人将死于此病。 Mekinist和Tafinlar被用于阻断相同分子通路的不同部位的信号促进癌细胞生长。它们特别适用作为联合治疗肿瘤表达基因突变被称为BRAF V600E和V600K黑色素瘤患者。BRAF蛋白质涉及在正常细胞生长中调节，但在约半数来自皮肤黑色素瘤突变。 FDA的药物评价和研究中心血液学和肿瘤室主任Richard Pazdur，医学博士说：“Mekinist和Tafinlar是被批注联合治疗黑色素瘤的第一个药物。”“它们为联合使用的发展是根据疾病的生物学通路强有力了解。这个批准说明继续研究药物为临床发展联合的价值。” 在162例有BRAF V600E和V600K突变有不可切除的或转移黑色素瘤参加者的临床试验中证实Mekinist与Tafinlar联用的安全性和有效性，参加者大多数没有接受既往治疗。参加者接受或 Mekinist与Tafinlar联用和Tafinlar作为单药直至他们的黑色素瘤进展和副作用变成不能耐受。 结果显示用Mekinist与Tafinlar联用治疗的参加者76%有其癌皱缩和消失(客观反应)平均持续10.5个月。相反，54 %参加者用Tafinlar作为单药治疗经历客观反应平均持续5.6个月。正在进行临床试验确定Mekinist与Tafinlar联用是否改进生存。 接受Mekinist与Tafinlar联用参加者报道的最常见副作用包括发热，畏寒，疲倦，皮疹，恶心，呕吐，腹泻，腹痛，外周性水肿(手和足肿胀)，咳嗽，头痛，关节痛，夜汗，食欲减低，便秘和肌肉痛。临床试验期间，当Mekinist与Tafinlar联合使用发热的发生率和严重程度增加。 严重副作用包括出血，凝块形成，心衰，皮肤问题和眼问题。Tafinlar的严重副作用之一—皮肤新鳞状细胞癌的发展—当药物与Mekinist联合使用时减少；这与这些两个药物在靶向分子通路的作用一致。在本试验联用时疲乏鳞状细胞癌发生率为7%与之比较用单药时19%。其他临床意义副作用包括肾受损。 应忠告生育能力妇女Mekinist和Tafinlar在发育胎儿中至出生缺陷。还应忠告男性和妇女Mekinist和Tafinlar治疗可能致不孕不育。 FDA在监管局加快批准程序下批准Mekinist和Tafinlar的联用，此程序根据临床数据显示该药物有某个对某个替代性终点有理由预测患者临床获益时允许FDA批准某药治疗某种严重疾病。这个程序提供患者较早得到有前途新药而公司进行验证性临床试验。FDA还在监管局的优先审评下审评这个药物联用，因为它们显示潜能在治疗一种显著严重情况中改进安全性和有效性。 Mekinist和Tafinlar有总部在北卡罗来纳州研究三角区GlaxoSmithKline公司上市。 附：完整资料； 1）：http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204114s001lbl.pdf 2）：https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aeaf0430-f8ad-4e72-9dbf-1954503c3410 ------------------------------------------------- 产地国家：美国 原产地英文商品名: Mekinist 0.5mg 30tablets 原产地英文药品名: TRAMETINIB 中文参考商品译名: Mekinist 0.5毫克/片 30片/瓶 中文参考药品译名: 曲美替尼 生产厂家英文名: 葛兰素史克 生产厂家英文名: GlaxoSmithKline ------------------------------------------------- 产地国家：美国 原产地英文商品名: Mekinist 1mg 30tablets 原产地英文药品名: TRAMETINIB 中文参考商品译名: Mekinist 1毫克/片 30片/瓶 中文参考药品译名: 曲美替尼 生产厂家英文名: 葛兰素史克 生产厂家英文名: GlaxoSmithKline ------------------------------------------------- 产地国家：美国 原产地英文商品名: Mekinist 2mg 30tablets 原产地英文药品名: TRAMETINIB 中文参考商品译名: Mekinist 2毫克/片 30片/瓶 中文参考药品译名: 曲美替尼 生产厂家英文名: 葛兰素史克 生产厂家英文名: GlaxoSmithKline ------------------------------------------------- 产地国家：美国 原产地英文商品名: Mekinist 0.5mg 30tablets 原产地英文药品名: TRAMETINIB 中文参考商品译名: Mekinist 0.5毫克/片 30片/瓶 中文参考药品译名: 曲美替尼 生产厂家英文名: 诺华制药 生产厂家英文名: Novartis Pharmaceuticals ------------------------------------------------- 产地国家：美国 原产地英文商品名: Mekinist 2mg 30tablets 原产地英文药品名: TRAMETINIB 中文参考商品译名: Mekinist 2毫克/片 30片/瓶 中文参考药品译名: 曲美替尼 生产厂家英文名: 诺华制药 生产厂家英文名: Novartis Pharmaceuticals