批准日期：2013年5月29日；公司: GlaxoSmithKline
FDA药物评价和研究中心血液学和肿瘤产品室主任Richard Pazdur，M.D.说：“我们对一种疾病的生物途径的认识进步已允许发展第三和第四个药物Tafinlar和Mekinist，在过去两年FDA已批准为治疗转移黑色素瘤。”
FDA的装置和放射性卫生中心体外诊断装置和放射学卫生室主任Alberto Gutierrez，Ph.D.说：“Tafinlar和Mekinist与对BRAF突变检测的第二个诊断伴侣共同批准证实和诊断伴侣检测和靶向癌的分子驱动物发展产品的医药承诺”。
处方资料重点
这些重点不包括安全和有效使用MEKINIST所需所有资料。请参阅下文为MEKINIST的完整处方资料
MEKINIST(trametinib)片，为口服使用
美国初始批准：2013
适应证和用途
MEKINIST是一种适用于治疗有不可切除的或转移黑色素瘤当用FDA批准测试检验有BRAF V600E或V600K突变患者。 (1)
使用限制：MEKINIST不适用于治疗以前曾接受BRAF抑制剂治疗患者。 (1)
剂量和给药方法
（1）开始用MEKINIST治疗前确证在肿瘤标本存在BRAF V600E或V600K突变。(2.1)
（2）推荐剂量是2 mg口服每天1次服用至少1小时前或进餐后至少2小时。(2.2)
注：(BRAF是一个人基因使一种被称为B-Raf的蛋白。基因还称为原-癌基因B-Raf和v-Raf鼠类肉瘤病毒原癌基因同源B1, 而这个蛋白更以前被称为丝氨酸/苏氨酸蛋白激酶B-Raf。)
剂型和规格
片：0.5mg，1mg，和2mg。(3)
禁忌证
无。 (4)
警告和注意事项
（1）心肌病：一个月治疗后再评估LVEF，和其后约每2至3个月评价。(5.1)
（2）视网膜色素上皮脱落(RPED)：对任何视觉障碍进行眼科评价。如被诊断RPED不给MEKINIST和如3个月后无改善终止。(5.2)
（3）视网膜静脉阻塞(RVO)：终止MEKINIST. (5.3)
（4）间质性肺疾病(ILD)：不给MEKINIST对新或进展性不能解释的肺症状或发现，例如咳嗽，呼吸困难，缺氧，或浸润。为治疗-相关ILD或肺炎永远终止MEKINIST。(5.4)
（5）严重皮肤毒性：监视皮肤毒性和继发感染。对不能耐受2级，或3或4级皮疹尽管MEKINIST的中止在3周内未改善终止。(5.5)
（6）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潜在风险。(5.6，8.1，8.6)
不良反应
对MEKINIST最常见不良反应(≥20%)包括皮疹，腹泻，和淋巴水肿。(6.1)
为报告怀疑不良反应，联系GlaxoSmithKline电话1-888-825-5249或FDA电话1-800-FDA-1088或www.fda.gov/medwatch.
特殊人群中使用
（1）哺乳母亲：终止药物或哺乳。(8.3)
（2）女性和男性的生殖潜能：忠告女性患者对妊娠计划和预防。可能损害生育能力。(8.6)
一般描述
Trametinib 二甲亚砜是一种激酶抑制剂。化学名是acetamide，N-[3-[3cyclopropyl-5-[(2-fluoro-4- iodophenyl)amino]-3,4,6,7-tetrahydro-6,8-dimethyl- 2,4,7trioxopyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl]-，compound with 1,1’-sulfinylbis[methane] (1:1)。分子式C26H23FIN5O4•C2H6OS与分子量693.53。Trametinib二甲亚砜结构如下：

Trametinib二甲亚砜是白色至几乎白色粉。实际上不溶于在pH范围2至8水介质。
MEKINIST(trametinib) 片以0.5-mg，1-mg，和2-mg片供应为口服给药。每0.5-mg片含0.5635 mg trametinib二甲亚砜等同于0.5 mg trametinib非溶剂化母体。每1-mg片含1.127 mg trametinib二甲亚砜等同于1 mg trametinib非溶剂化母体。每2-mg片含2.254 mg trametinib二甲亚砜等同于2 mg trametinib非溶剂化母体。
MEKINIST 片的无活性成分是：片芯：甘露醇，微晶纤维素，羟丙甲纤维素，交联羧甲基纤维素钠，硬脂酸镁(植物来源)，月桂基硫酸钠，胶态二氧化硅。涂层：羟丙甲纤维素，二氧化钛，聚乙二醇，聚山梨醇80(2-mg片)，黄色氧化铁(0.5-mg片)，红色氧化铁(2-mg片)。
作用机制
Trametinib 是一种有丝分裂原-激活的胞外信号调控激酶1(MEK1)和MEK2激活以及MEK1和MEK2激酶活性的可逆性抑制。MEK蛋白胞外信号-相关激酶 (ERK)通路的上游调节物，促进细胞增殖作用。BRAF V600E突变导致BRAF通路的结构性激活其中包括MEK1和MEK2。Trametinib抑制BRAF V600突变-阳性黑色素瘤细胞在体外和体内生长。
Pharmacological Class:
Kinase inhibitor.

Active Ingredient(s):
Trametinib 0.5mg, 1mg, 2mg; tabs.

Company
GlaxoSmithKline Pharmaceuticals
Indication(s):
Treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. Limitation of use: not indicated for the treatment of patients who have received prior BRAF-inhibitor therapy.

Pharmacology:
Trametinib is a reversible inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation and of MEK1 and MEK2 kinase activity. Trametinib inhibits BRAF V600 mutation-positive melanoma cell growth in vitro and in vivo.

Clinical Trials:
The safety and efficacy of Mekinist were eva luated in an international, multicenter, randomized (2:1), open label, active-controlled trial in 322 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma. Patients were not permitted to have more than one prior chemotherapy regimen for advanced or metastatic disease; prior treatment with a BRAF inhibitor or MEK inhibitor was not ­permitted.

The primary efficacy outcome measure was progression-free survival (PFS). Patients were randomized to Mekinist 2mg once daily (N = 214) or chemotherapy (N = 108) consisting of either dacarbazine 1,000mg/m2 IV every 3 weeks or paclitaxel 175mg/m2 IV every 3 weeks. Treatment continued until disease progression or unacceptable toxicity. Tumor samples from 289 patients (196 = Mekinist; 93 = chemotherapy-treated) were also tested retrospectively using an FDA-approved companion diagnostic test, THxID-BRAF assay.

The study demonstrated a statistically significant increase in PFS in patients treated with Mekinist. In terms of PFS, the Mekinist treatment arm showed a lower number of events (disease progression or death), in terms of percentage, compared to the chemotherapy treatment arm (55% [117/214] vs. 71% [77/108]), respectively. Also, the Mekinist treatment arm showed a longer median PFS compared to the chemotherapy arm (4.8 months vs. 1.5 months), respectively (HR 0.47, [95% CI: 0.34, 0.65], P<0.0001). For confirmed tumor responses, the Mekinist treatment arm showed a higher objective response rate compared to the chemotherapy treatment arm (22% [95% CI: 17, 28] vs. 8% [95% CI: 4, 15], respectively), with 4 patients from the Mekinist arm achieving complete response and no complete responses from the chemotherapy arm.

For more information on clinical trials, see full labeling.

Legal Classification:
Rx

Adults:
Confirm presence of BRAF V600E or V600K mutation prior to initiation. Take at least 1 hour before or 2 hours after a meal. 2mg once daily until disease progression or unacceptable toxicity. Dose modifications: see full labeling.

Children:
Not established.

Warnings/Precautions:
Risk of cardiomyopathy; assess LVEF prior to initiation, after one month, and then at every 2–3 month intervals during treatment; withhold if absolute LVEF decreases by 10% from pre-treatment values and is less than the lower limit of normal; permanently discontinue if symptomatic cardiomyopathy or persistent asymptomatic LVEF dysfunction is unresolved within 4 weeks. Perform eye exam at any time for visual disturbances and compare to baseline. Retinal pigment epithelial detachment; withhold if diagnosed; if resolved within 3 weeks, may resume at reduced dose. Withhold if new or progressive pulmonary symptoms or findings develop. Permanently discontinue if retinal vein occlusion, interstitial lung disease, or pneumonitis occurs. Monitor for skin toxicities and secondary infections. Embryo-fetal toxicity. Females of reproductive potential should use highly effective contraception during and for 4 months after treatment. Pregnancy (Category D). Nursing mothers: not recommended.

Adverse Reaction(s)
Rash, diarrhea, lymphedema.

How Supplied:
Tabs—30

LAST UPDATED:
9/17/2013