温馨提醒：本说明书仅供参考，最新的说明书详见药品附带的说明书。

1适应症和用途

MEKTOVI ®被指示时，在与组合encorafenib，用于患者的治疗不可切除或转移性黑色素瘤与BRAF V600E或V600K突变，由FDA批准的试验所检测[见剂量和给药方法（2.1） ]。

2用法用量

2.1患者选择

在启动MEKTOVI之前，先确认肿瘤标本中存在BRAF V600E或V600K突变[临床研究（14）]。有关FDA批准的用于检测黑色素瘤中BRAF V600E和V600K突变的测试的信息，请访问：http://www.fda.gov/CompanionDiagnostics。

2.2推荐剂量

MEKTOVI的推荐剂量为45 mg，每天口服两次，相隔约12小时，与encorafenib联合使用，直至疾病进展或出现不可接受的毒性。有关推荐的encorafenib剂量信息，请参阅encorafenib的处方信息。

MEKTOVI可以与食物一起或不与食物一起服用[见临床药理学（12.3） ]。不要在下一次服用MEKTOVI后6小时内服用错过的MEKTOVI。

如果在服用MEKTOVI后出现呕吐，请不要再服用其他剂量，而应继续下一个计划的剂量。

2.3不良反应的剂量修改

如果encorafenib永久停用，请停用MEKTOVI。

表1列出了与MEKTOVI相关的不良反应的剂量减少。

表1：建议MEKTOVI减少不良反应的剂量

表2列出了与MEKTOVI相关的不良反应的剂量调整方法。

表2：MEKTOVI对不良反应的推荐剂量修改

请参阅依可拉非尼的处方信息，以调整与依可拉非尼相关的不良反应的剂量。

2.4中度或重度肝功能不全的剂量调整

对于中度（总胆红素大于1.5且小于或等于3×ULN和任何AST）或严重（总胆红素水平大于3×ULN和任何AST）肝功能不全的患者，推荐剂量为30 mg口服两次每天[见在特定人群中使用（8.6），临床药理学（12.3） ]。

3剂型和强度

片剂：15毫克，黄色/深黄色，未刻痕的双凸椭圆形薄膜衣片，一侧凹有程式化的“ A”，另一侧凹有“ 15”。

4禁忌症

没有。

5警告和注意事项

5.1心肌病

据报道，MEKTOVI联合恩可拉非治疗的患者出现心肌病，表现为左心功能不全，伴有症状或无症状的射血分数降低。在COLUMBUS中，有7％的接受MEKTOVI加恩可拉非尼的患者出现了心肌病的证据（LVEF降低至低于机构性LLN，而超声心动图或MUGA检测到LVEF绝对降低至基线以下10％以上）。1.6％的患者发生3级左心功能不全。接受MEKTOVI合并恩可拉非尼的患者首次出现左心功能不全（任何级别）的中位时间为3.6个月（0至21个月）。接受MEKTOVI加恩可拉非尼治疗的患者中有87％的心肌病得到了缓解。

在开始治疗前，开始治疗后一个月，然后在治疗期间每2至3个月通过超声心动图或MUGA扫描评估射血分数。对于基线射血分数低于50％或低于正常机构下限（LLN）的患者，尚未确定MEKTOVI与encorafenib联用的安全性。使用MEKTOVI治疗时，应密切监测具有心血管危险因素的患者。

根据不良反应的严重程度，停药，减少剂量或永久中止[参见剂量和用法（2.3），不良反应（6.1） ]。

5.2静脉血栓栓塞

在COLUMBUS中，接受MEKTOVI并与encorafenib联用的患者中有6％发生了静脉血栓栓塞（VTE），其中有3.1％的患者发生了肺栓塞。根据不良反应的严重程度，停药，减少剂量或永久中止[参见剂量和用法（2.3），不良反应（6.1） ]。

5.3眼毒性

浆液性视网膜病

在COLUMBUS中，MEKTOVI与恩可拉非尼联合治疗的患者中有20％发生浆液性视网膜病变。视网膜脱离占8％，黄斑水肿占6％。有症状的浆液性视网膜病发生率为8％，无失明病例。没有患者因浆液性视网膜病变而停药。6％的患者需要中断剂量或降低剂量。首次发生浆液性视网膜病变（所有级别）的中位时间为1.2个月（范围为0到17.5个月）。

每次就诊时评估视觉症状。定期进行眼科检查，检查是否有新的或恶化的视力障碍，并跟踪新的或持续的眼科检查结果。根据不良反应的严重程度，停药，减少剂量或永久中止[参见剂量和用法（2.3），不良反应（6.1） ]。

视网膜静脉阻塞

RVO是已知的与MEK抑制剂有关的分类不良反应，可能在接受MEKTOVI和恩可拉非联合治疗的患者中发生。在接受MEKTOVI和encorafenib治疗的BRAF突变阳性黑色素瘤患者中（n = 690），有1例患者出现RVO（0.1％）。

既往有RVO病史或当前RVO危险因素包括不受控制的青光眼或有高粘度或高凝综合征的病史的患者，尚未确定MEKTOVI的安全性。

在24小时内对患者报告的急性视力丧失或其他视力障碍进行眼科评估。记录有RVO的患者永久中止MEKTOVI [见剂量和用法（2.3），不良反应（6.1） ]。

葡萄膜炎

据报道，MEKTOVI与恩可拉非尼联合治疗的患者出现葡萄膜炎，包括虹膜炎和虹膜睫状体炎。在COLUMBUS中，MEKTOVI与恩可拉非尼联合治疗的患者中葡萄膜炎的发生率为4％。

每次就诊时评估视觉症状。定期进行眼科评估，检查是否有新的或恶化的视觉障碍，并跟踪新的或持续的眼科检查结果。根据不良反应的严重程度，停药，减少剂量或永久中止[参见剂量和用法（2.3），不良反应（6.1） ]。

5.4间质性肺疾病

在接受MEKTOVI和encorafenib的BRAF突变阳性黑色素瘤患者（n = 690）中，有2名患者（0.3％）发展为间质性肺病（ILD），包括肺炎。

评估新的或进行性无法解释的肺部症状或可能的ILD的发现。根据不良反应的严重程度，停药，减少剂量或永久中止[参见剂量和用法（2.3），不良反应（6.1） ]。

5.5肝毒性

当MEKTOVI与恩可拉非尼合用时，可能发生肝毒性。在COLUMBUS中，接受MEKTOVI并与encorafenib联用的患者在肝功能实验室检查中发生3或4级升高的发生率是丙氨酸转氨酶（ALT）为6％，天冬氨酸转氨酶（AST）为2.6％，碱性磷酸酶为0.5％。没有患者出现3级或4级血清胆红素升高。

在开始MEKTOVI之前，治疗期间每月并根据临床指示监测肝实验室检查。根据不良反应的严重程度，停药，减少剂量或永久中止[参见剂量和用法（2.3），不良反应（6.1） ]。

5.6横纹肌溶解

当MEKTOVI与恩可拉非尼联合使用时，可能会发生横纹肌溶解。在COLUMBUS中，MEKTOVI与恩可拉非尼联合治疗的患者中58％的血清CPK实验室值升高。在接受MEKTOVI和encorafenib治疗的BRAF突变阳性黑色素瘤患者中（n = 690），据报道有1名患者发生横纹肌溶解（0.1％）。

在开始MEKTOVI之前，治疗期间和临床指示期间定期监测CPK和肌酐水平。根据不良反应的严重程度，停药，减少剂量或永久中止[参见剂量和用法（2.3），不良反应（6.1） ]。

5.7出血

MEKTOVI与恩可拉非尼合用时可能会发生出血。在COLUMBUS中，接受MEKTOVI联合encorafenib的患者中有19％发生出血。3.2％的患者发生3级以上出血。最常见的出血事件是胃肠道疾病，包括直肠出血（4.2％），便血（3.1％）和痔疮出血（1％）。在发生新的或进行性脑转移的情况下，致命的颅内出血发生在1.6％的患者中。

根据不良反应的严重程度，停药，减少剂量或永久中止[参见剂量和用法（2.3），不良反应（6.1） ]。

5.8胚胎-胎儿毒性

根据动物研究的结果及其作用机理，MEKTOVI给予孕妇时可能引起胎儿伤害。当在器官形成期间以大于或等于剂量的剂量对兔子给药时，比尼美替尼具有胚胎毒性和流产作用，其剂量约为每天两次建议的45 mg临床剂量，其暴露量约为人暴露量的5倍。

建议妇女注意胎儿的潜在危险。繁殖潜力的提醒女MEKTOVI治疗过程中使用有效的避孕和为最终给药后至少30天[见特殊人群中使用（8.1，8.3） ]。

5.9联合治疗相关的风险

MEKTOVI被指定与恩可拉非尼联合使用。有关适用于联合使用治疗的其他风险信息，请参阅encorafenib处方信息。

6不良反应

标签上其他地方描述了以下不良反应：

• 心肌病[请参阅警告和注意事项（5.1） ]
• 静脉血栓栓塞[请参阅警告和注意事项（5.2） ]
• 眼毒性[见警告和注意事项（5.3） ]
• 间质性肺疾病[请参阅警告和注意事项（5.4） ]
• 肝毒性[参见警告和注意事项（5.5） ]
• 横纹肌溶解[请参阅警告和注意事项（5.6） ]
• 出血[请参阅警告和注意事项（5.7） ]

6.1临床试验经验

由于临床试验是在广泛不同的条件下进行的，因此无法将在某种药物的临床试验中观察到的不良反应率直接与另一种药物的临床试验中观察到的不良反应率进行比较，并且可能无法反映实际中观察到的不良反应率。

警告和注意事项中的数据[请参见警告和注意事项（5） ]反映了192例BRAF V600突变阳性的不可切除或转移性黑色素瘤患者与恩考拉尼（450 mg每天一次）联合使用MEKTOVI（每天两次45 mg）。一项随机的，开放标签，活动，对照试验（COLUMBUS），或在罕见情况下，将300毫克至600毫克剂量的690名BRAF V600突变阳性黑色素瘤患者与encorafenib联合接受MEKTOVI（每天两次，每次45 mg）每天多次进行多次临床试验。

下文所述数据反映了COLUMBUS中192例BRAF V600突变阳性的不可切除或转移性黑色素瘤患者与恩可拉非尼（450 mg每天一次）联合使用MEKTOVI（45 mg每天两次）。

COLUMBUS试验[参见临床研究（14） ]排除了具有吉尔伯特综合症病史，左心室射血分数异常，QTc延长（> 480毫秒），高血压不受控制以及视网膜静脉阻塞的病史或当前证据的患者。MEKTOVI联合恩可拉非尼治疗的患者中位暴露时间为11.8个月，维拉非尼治疗的患者中位暴露时间为6.2个月。

接受MEKTOVI合并恩可拉非的患者最常见（≥25％）不良反应为疲劳，恶心，腹泻，呕吐和腹痛。

接受MEKTOVI合并恩可拉非尼的患者中有33％发生了导致MEKTOVI剂量中断的不良反应。最常见的是左心功能不全（6％）和浆液性视网膜病变（5％）。接受恩可拉非尼联用的MEKTOVI患者中有19％发生不良反应，导致MEKTOVI剂量降低；最常见的是左心功能不全（3％），浆液性视网膜病变（3％）和结肠炎（2％）。接受MEKTOVI与恩可拉非尼合用的患者中有5％（5％）出现不良反应，导致MEKTOVI永久停药。导致MEKTOVI永久停药的最常见不良反应是2％的出血和1％的头痛。

表3和表4分别显示了在COLUMBUS中鉴定出的药物不良反应和实验室异常。COLUMBUS试验的目的不是表3列出的任何特定不良反应，与vemurafenib相比，MEKTOVI联合encorafenib的不良反应率在统计学上有显着差异。

表3：在哥伦布中≥10％接受MEKTOVI并与恩可拉非联合治疗的患者发生不良反应*

在接受MEKTOVI并恩可拉非尼联合治疗的患者中，发生在<10％的患者中发生的其他临床上重要的不良反应是：

胃肠道疾病：结肠炎

皮肤和皮下组织疾病：脂膜炎

免疫系统疾病：药物超敏反应

表4：在哥伦布接受MEKTOVI合并恩可拉非治疗的患者中≥10％（所有年级）发生的实验室异常*

7药物相互作用

尚未观察到MEKTOVI具有临床上重要的药物相互作用。

8在特定人群中的使用

8.1怀孕

风险摘要

基于动物繁殖研究的发现及其作用机理，MEKTOVI给予孕妇时可引起胎儿伤害[见临床药理学（12.1） ]。没有关于怀孕期间使用MEKTOVI的可用临床数据。在动物生殖研究中，宾尼替尼在器官发生期间的口服给药具有胚胎毒性，并且对兔子的流产作用大于或等于在临床剂量为每天45 mg两次时人体暴露量约为人类暴露量5倍的剂量（参见数据）。建议孕妇注意胎儿的潜在危险。

在美国普通人群中，临床公认的怀孕中主要先天缺陷和流产的估计背景风险分别为2％至4％和15％至20％。

数据

动物资料

在生殖毒性研究中，在器官发生期间对大鼠施用比美替尼会导致母体毒性，胎儿体重减少和骨化变化增加（≥30 mg / kg /天）（建议使用基于AUC的人体暴露量的37倍） 45毫克的临床剂量，每天两次）。在怀孕的兔子中，比米替尼的给药在器官发生期间导致母体毒性，胎儿体重下降，畸形增加以及植入后损失增加，包括≥10 mg / kg /天的剂量导致的全部妊娠流失（约为人类暴露量的5倍）。建议的临床剂量AUC每天两次，每次45 mg。每天20 mg / kg /天的宾尼替尼，胎儿心室间隔缺损和肺干改变显着增加（在建议的45 mg每天两次的临床剂量下，比人暴露量少8倍）。

8.2哺乳

风险摘要

没有关于人乳中存在宾尼替尼或其活性代谢物，宾尼替尼对母乳喂养婴儿或产奶量的影响的数据。由于对母乳喂养的婴儿来说，MEKTOVI可能会引起严重的不良反应，因此建议女性在用MEKTOVI治疗期间以及最终剂量后3天不要母乳喂养。

8.3生殖潜力的男性和女性

验孕

在开始使用 MEKTOVI之前，请验证具有生殖潜力的女性的怀孕状况[请参阅在特定人群中使用（8.1） ]。

避孕

给孕妇服用时，MEKTOVI可能会造成胎儿伤害[请参见“ 在特定人群中使用（8.1）” ]。

女性

劝告有生殖潜力的女性在用MEKTOVI治疗期间以及最终剂量后至少30天内使用有效的避孕方法。

8.4小儿使用

尚未在小儿患者中确定MEKTOVI的安全性和有效性。

8.5老年人使用

在多个临床试验中，每天接受300毫克至600毫克剂量的MEKTOVI（45毫克每天两次）联合encorafenib的690例BRAF突变阳性黑色素瘤患者在多项临床试验中接受治疗，其中20％的患者年龄在65-74岁之间，而8％的患者年龄在75岁以上。与年轻患者相比，老年患者未观察到MEKTOVI加恩可拉非尼的安全性或有效性的总体差异[见临床药理学（12.3） ]。

8.6肝功能不全

中度或重度肝功能不全患者的Binimetinib浓度可能会增加。对于轻度肝功能不全（总胆红素> 1且≤1.5×ULN且任何AST或总胆红素≤ULN且AST> ULN）的患者，不建议调整MEKTOVI的剂量。对于中度（总胆红素> 1.5且≤3×ULN和任何AST）或重度（总胆红素水平> 3×ULN和任何AST）肝功能不全的患者，降低MEKTOVI的剂量[见剂量和给药方法（2.4），临床药理学（（12.3） ]。

10过量

由于比尼替尼 97％与血浆蛋白结合，因此血液透析在用MEKTOVI过量治疗中可能无效。

11说明

Binimetinib是一种激酶抑制剂。化学名称是5-[（4-溴-2-氟苯基）氨基] -4-氟-N-（2-羟基乙氧基）-1-甲基-1H-苯并咪唑-6-甲酰胺。分子式为C 17 H 15 BrF 2 N 4 O 3，分子量为441.2道尔顿。Binimetinib的化学结构如下所示：

Binimetinib是白色至浅黄色粉末。在水性介质中，比尼美替尼在pH 1时微溶，在pH 2时微溶，在pH 4.5和更高时几乎不溶。

口服的MEKTOVI（Binimetinib）片剂含有15 mg的Binimetinib和以下非活性成分：乳糖一水合物，微晶纤维素，交联羧甲基纤维素钠，硬脂酸镁（植物来源）和胶体二氧化硅。该涂层包含聚乙烯醇，聚乙二醇，二氧化钛，滑石粉，氧化铁黄和氧化铁铁。

12临床药理学

12.1行动机制

Binimetinib是一种有丝分裂原激活的细胞外信号调节激酶1（MEK1）和MEK2活性的可逆抑制剂。MEK蛋白是细胞外信号相关激酶（ERK）途径的上游调节剂。在体外，binimetinib在无细胞试验中抑制了细胞外信号相关激酶（ERK）的磷酸化，并抑制了BRAF突变型人黑素瘤细胞系的活力和MEK依赖性磷酸化。Binimetinib还可以抑制BRAF突变型鼠异种移植模型的体内ERK磷酸化和肿瘤生长。

Binimetinib和encorafenib靶向RAS / RAF / MEK / ERK途径中的两个不同的激酶。与单独使用任何一种药物相比，encorafenib和Binimetinib的共同给药在体外对BRAF突变阳性细胞系具有更高的抗增殖活性，并在小鼠中对BRAF V600E突变型人黑素瘤异种移植研究产生了更大的抗肿瘤活性。此外，比尼米替尼和恩哥拉非尼的组合与单独使用任何一种药物相比，都延迟了小鼠BRAF V600E突变型人黑素瘤异种移植物中耐药性的出现。

12.2药效学

心脏电生理学

每天两次MEKTOVI 45 mg后，未观察到具有临床意义的QT延长。

12.3药代动力学

在健康受试者和实体瘤患者中研究了宾尼替尼的药代动力学。每天两次给药后，在稳态下的累积量是1.5倍，浓度-时间曲线（AUC）下面积的变异系数（CV％）<40％。比尼替尼的全身暴露与剂量成正比。

吸收性

口服给药后，至少50％的比美替尼剂量被吸收，中位时间达到1.6小时的最大浓度（T max）。

食物的作用

在健康受试者中单剂量服用45毫克MEKTOVI和高脂肪，高热量的餐食（大约150卡路里来自蛋白质，350卡路里来自碳水化合物和500卡路里来自脂肪）对比尼替尼的暴露没有影响。

分配

Binimetinib与人血浆蛋白的结合率为 97％，血液与血浆的比率为0.72。比美替尼表观分布体积的几何平均值（CV％）为92 L（45％）。

消除

比尼美替尼的平均（CV％）终末半衰期（t 1/2）为3.5小时（28.5％），表观清除率（CL / F）为20.2 L / h（24％）。

代谢

主要的代谢途径是葡萄糖醛酸化，UGT1A1 占比尼美替尼代谢的61％。Binimetinib代谢的其他途径包括N-脱烷基化，酰胺水解以及侧链上的乙二醇损失。由CYP1A2和CYP2C19产生的活性代谢产物M3占Binimetinib暴露量的8.6％。单次口服45 mg放射性标记的比米替尼后，血浆中循环放射性AUC的约60％可归因于比米替尼。

排泄

在健康受试者中单次口服45 mg放射性标记的Binimetinib后，粪便中回收的剂量为62％（不变32％），而尿液中回收了31％（不变6.5％）。

特定人群

年龄（20至94岁），性别或体重对比美替尼的全身暴露没有重要的临床意义。种族或族裔对比尼替尼药代动力学的影响尚不清楚。

肝功能不全：与轻度肝功能不全（总胆红素> 1且≤1.5×ULN且任何AST或总胆红素≤ULN和AST> ULN）相比，未观察到比尼美替尼暴露（AUC和C max）在临床上无有意义的变化肝功能正常的受试者（总胆红素≤ULN和AST≤ULN）。患有中度（总胆红素> 1.5且≤3×ULN和任何AST）或严重（总胆红素水平> 3×ULN和任何AST）肝功能不全的受试者观察到AUC升高2倍[参见剂量和给药方法（2.4 ） ]。

肾功能不全：与具有正常肾功能的受试者相比，在严重肾功能不全（eGFR≤29 mL / min / 1.73 m 2）的受试者中，未观察到比尼美替尼暴露的临床重要变化。

药物相互作用研究

临床研究

UGT1A1诱导剂或抑制剂对Binimetinib的影响：UGT1A1基因型和吸烟（UGT1A1诱导剂）对Binimetinib的暴露没有临床重要影响。模拟预测类C 最大的binimetinib 45毫克在阿扎那韦400毫克（UGT1A1抑制剂）的存在或不存在。

在无差异binimetinib时MEKTOVI与encorafenib共同给予曝光已被观察到。

的效果Binimetinib对CYP的基材：Binimetinib没有改变敏感CYP3A4底物（咪达唑仑）的曝光。

减酸剂对Binimetinib的影响：在存在胃酸减少剂（雷贝拉唑）的情况下，binimetinib的暴露程度（AUC）不变。

体外研究

的效果Binimetinib对CYP的底物： Binimetinib不是CYP1A2，CYP2C9，CYP2D6或CYP3A的依赖于时间的抑制剂。

转运 蛋白对Binimetinib的影响：Binimetinib是P-糖蛋白（P-gp）和乳腺癌抗性蛋白（BCRP）的底物。Binimetinib不是有机阴离子转运多肽（OATP1B1，OATP1B3，OATP2B1）或有机阳离子转运蛋白1（OCT1）的底物。

13毒理学

13.1致癌，诱变，生育力受损

尚未进行比米替尼致癌性研究。在评估细菌的反向突变，哺乳动物细胞中的染色体畸变或大鼠骨髓中的微核的研究中，比尼替尼没有遗传毒性。

尚未对比尼替尼在动物中进行专门的生育力研究。在大鼠和猴子的一般毒理学研究中，在雄性或雌性生殖器官中均未见明显发现。

14临床研究

在一项随机，主动控制，开放标签，多中心试验（COLUMBUS； NCT01909453）中评估了MEKTOVI与恩可拉非的组合。使用bioMerieux THxID™BRAF分析检测出的合格患者必须患有BRAF V600E或V600K突变阳性的不可切除或转移性黑色素瘤。允许患者在辅助条件下接受免疫治疗，并在先前的免疫治疗方案中接受不可切除的局部晚期或转移性疾病的治疗。禁止事先使用BRAF抑制剂或MEK抑制剂。根据美国癌症联合委员会（AJCC）阶段（IIIB，IIIC，IVM1a或IVM1b，对比IVM1c），东部合作肿瘤小组（ECOG）的表现状态（0对1）以及先前针对无法切除或转移性疾病的免疫疗法（是与否）。

患者被随机（1：1：1）接受每日两次MEKTOVI 45 mg联合恩可拉非尼450 mg每日一次（MEKTOVI联合encorafenib），依可拉非尼300 mg每天一次或维拉非尼960 mg每日两次。继续治疗直至疾病进展或不可接受的毒性。下面仅描述批准的给药结果（MEKTOVI 45 mg与恩可拉非450 mg联用）。

主要功效结局指标是无进展生存期（PFS），通过盲法独立中央评价进行评估，以比较MEKTOVI与恩可拉非尼与维拉非尼联合使用。其他疗效指标包括总体生存率（OS）以及客观缓解率（ORR）和缓解持续时间（DoR），这些均通过集中评估进行评估。

总共577例患者被随机分配，其中192例与恩可拉非尼联合应用到MEKTOVI中，194例与encorafenib联合使用，191例与维拉非尼治疗。在383名随机接受MEKTOVI联合encorafenib或vemurafenib治疗的患者中，中位年龄为56岁（20至89岁），其中男性为59％，白人为91％，基线ECOG表现为72％。 0. 95％（95％）有转移性疾病，65％为IVM1c期，4％接受了先前的CTLA-4，PD-1或PD-L1定向抗体。28％（28％）的基线血清乳酸脱氢酶（LDH）升高，45％的基线≥3个器官受累于肿瘤，3％的患者发生脑转移。根据集中测试，100％的患者肿瘤BRAF突变检测为阳性；BRAF V600E（88％），BRAF V600K（11％），或两者（<1％）。

与维拉非尼相比，MEKTOVI与恩可拉非尼合用显示出PFS的统计学显着改善。疗效结果总结在表5和图1中。

表5：COLUMBUS的疗效结果

图1：哥伦布无进展生存期的Kaplan-Meier曲线

16供应/存储和处理方式

MEKTOVI（Binimetinib）以15毫克黄色/深黄色无凹痕双凸椭圆形薄膜衣片形式供货，一侧压刻有程式化的“ A”，另一侧刻有“ 15”，每瓶180片（NDC 70255- 010-02）。

存放在20°C至25°C（68°F至77°F）; 允许在15°C至30°C（59°F至86°F）之间的偏移[请参阅USP控制的室温]。

17患者咨询信息

建议患者阅读FDA批准的患者标签（患者信息）。

通知患者以下内容：

心肌病

劝告患者向其医疗服务提供者报告任何心力衰竭症状[见警告和注意事项（5.1） ]。

静脉血栓形成

如果患者出现静脉血栓形成或肺栓塞的症状，建议他们与医疗保健提供者联系。建议患者因呼吸困难突然发作，腿痛或肿胀而寻求医疗救治[见警告和注意事项（5.2） ]。

眼毒性

如果患者视力有任何变化，建议他们联系他们的医疗保健提供者[见警告和注意事项（5.3） ]。

间质性肺疾病

如果患者出现任何新的或恶化的呼吸道症状，包括咳嗽或呼吸困难，建议患者联系其医疗保健提供者[请参阅警告和注意事项（5.4） ]。

肝毒性

劝告患者在MEKTOVI治疗期间建议进行血清肝检查（ALT，AST，胆红素）的系列检查。指示患者报告肝功能不全的症状，包括黄疸，尿色深，恶心，呕吐，食欲不振，疲劳，淤青或出血[见警告和注意事项（5.5） ]。

横纹肌溶解

如果患者出现异常或新发的虚弱，肌痛或尿液变黑，建议他们尽快与他们的医疗保健提供者联系[见警告和注意事项（5.6） ]。

出血

如果患者出现暗示出血的症状（例如异常出血），则建议患者通知其医疗服务提供者[请参阅警告和注意事项（5.7） ]。

生殖潜力的男性和女性

胚胎-胎儿毒性：建议具有生殖潜能的女性对胎儿有潜在危险。劝告有生殖潜力的女性在MEKTOVI治疗期间和最终剂量后的30天内使用有效的避孕方法。建议女性在使用MEKTOVI治疗期间怀孕或怀疑怀孕时联系其医疗保健提供者[请参阅警告和注意事项（5.8），在特定人群中使用（8.1） ]。

哺乳期：建议妇女在用MEKTOVI治疗期间和最终剂量后3天内不要母乳喂养[见在特定人群中使用（8.2） ]。

发行人：
Array BioPharma Inc.
核桃街3200号
，科罗拉多州80301

©2018 Array BioPharma Inc.保留所有权利。
MEKTOVI ®是阵列生物制药公司在美国及其他国家的注册商标。
获得专利。参见www.arraybiopharma.com/patents

主要显示面板-15毫克片剂瓶纸箱

NDC 70255-010-02

MEKTOVI ®
（binimetinib）片剂

15毫克

仅Rx

180片

【备注】以上内容仅供参考，不作为用药依据，详情请参照药品附带说明书。

本说明书来源于：美国FDA

https://nctr-crs.fda.gov/fdalabel/services/spl/set-ids/6c3408ac-d401-4925-8a03-26591afbc240/spl-doc?hl=Binimetinib

温馨提醒：

①建议您用 谷歌浏览器  在电脑上或手机  打开以上链接，就可以自动翻译成简体中文，而且翻译的还比较准确。

②本说明书仅供参考，最新的说明书详见药品附带的说明书。

1 INDICATIONS AND USAGE

MEKTOVI® is indicated, in combination with encorafenib, for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test [see Dosage and Administration (2.1)].

2 DOSAGE AND ADMINISTRATION

2.1 Patient Selection

Confirm the presence of a BRAF V600E or V600K mutation in tumor specimens prior to initiating MEKTOVI [Clinical Studies (14)]. Information on FDA-approved tests for the detection of BRAF V600E and V600K mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics.

2.2 Recommended Dosage

The recommended dosage of MEKTOVI is 45 mg orally taken twice daily, approximately 12 hours apart, in combination with encorafenib until disease progression or unacceptable toxicity. Refer to the encorafenib prescribing information for recommended encorafenib dosing information.

MEKTOVI may be taken with or without food [see Clinical Pharmacology (12.3)]. Do not take a missed dose of MEKTOVI within 6 hours of the next dose of MEKTOVI.

Do not take an additional dose if vomiting occurs after MEKTOVI administration but continue with the next scheduled dose.

2.3 Dosage Modifications for Adverse Reactions

If encorafenib is permanently discontinued, discontinue MEKTOVI.

Dose reductions for adverse reactions associated with MEKTOVI are presented in Table 1.

Table 1: Recommended Dose Reductions for MEKTOVI for Adverse Reactions

Dosage modifications for adverse reactions associated with MEKTOVI are presented in Table 2.

Table 2: Recommended Dosage Modifications for MEKTOVI for Adverse Reactions

Refer to the encorafenib prescribing information for dose modifications for adverse reactions associated with encorafenib.

2.4 Dosage Modifications for Moderate or Severe Hepatic Impairment

For patients with moderate (total bilirubin greater than 1.5 and less than or equal to 3 × ULN and any AST) or severe (total bilirubin levels greater than 3 × ULN and any AST) hepatic impairment, the recommended dosage is 30 mg orally taken twice daily [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

3 DOSAGE FORMS AND STRENGTHS

Tablets: 15 mg, yellow/dark yellow, unscored biconvex oval film-coated tablets debossed with a stylized "A" on one side and "15" on the other side.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Cardiomyopathy

Cardiomyopathy, manifesting as left ventricular dysfunction associated with symptomatic or asymptomatic decreases in ejection fraction, has been reported in patients treated with MEKTOVI in combination with encorafenib. In COLUMBUS, evidence of cardiomyopathy (decrease in LVEF below the institutional LLN with an absolute decrease in LVEF ≥ 10% below baseline as detected by echocardiography or MUGA) occurred in 7% of patients receiving MEKTOVI plus encorafenib. Grade 3 left ventricular dysfunction occurred in 1.6% of patients. The median time to first occurrence of left ventricular dysfunction (any grade) in patients receiving MEKTOVI in combination with encorafenib was 3.6 months (range 0 to 21 months). Cardiomyopathy resolved in 87% of patients receiving MEKTOVI plus encorafenib.

Assess ejection fraction by echocardiogram or MUGA scan prior to initiating treatment, one month after initiating treatment, and then every 2 to 3 months during treatment. The safety of MEKTOVI in combination with encorafenib has not been established in patients with a baseline ejection fraction that is either below 50% or below the institutional lower limit of normal (LLN). Patients with cardiovascular risk factors should be monitored closely when treated with MEKTOVI.

Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)].

5.2 Venous Thromboembolism

In COLUMBUS, venous thromboembolism (VTE) occurred in 6% of patients receiving MEKTOVI in combination with encorafenib, including 3.1% of patients who developed pulmonary embolism. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)].

5.3 Ocular Toxicities

Serous Retinopathy

In COLUMBUS, serous retinopathy occurred in 20% of patients treated with MEKTOVI in combination with encorafenib; 8% were retinal detachment and 6% were macular edema. Symptomatic serous retinopathy occurred in 8% of patients with no cases of blindness. No patient discontinued MEKTOVI due to serous retinopathy; 6% of patients required dose interruptions or dose reductions. The median time to onset of the first event of serous retinopathy (all grades) was 1.2 months (range 0 to 17.5 months).

Assess for visual symptoms at each visit. Perform an ophthalmologic examination at regular intervals, for new or worsening visual disturbances, and to follow new or persistent ophthalmologic findings. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)].

Retinal Vein Occlusion

RVO is a known class-related adverse reaction of MEK inhibitors and may occur in patients treated with MEKTOVI in combination with encorafenib. In patients with BRAF mutation-positive melanoma receiving MEKTOVI with encorafenib (n=690), 1 patient experienced RVO (0.1%).

The safety of MEKTOVI has not been established in patients with a history of RVO or current risk factors for RVO including uncontrolled glaucoma or a history of hyperviscosity or hypercoagulability syndromes.

Perform ophthalmologic evaluation for patient-reported acute vision loss or other visual disturbance within 24 hours. Permanently discontinue MEKTOVI in patients with documented RVO [see Dosage and Administration (2.3), Adverse Reactions (6.1)].

Uveitis

Uveitis, including iritis and iridocyclitis, has been reported in patients treated with MEKTOVI in combination with encorafenib. In COLUMBUS, the incidence of uveitis among patients treated with MEKTOVI in combination with encorafenib was 4%.

Assess for visual symptoms at each visit. Perform an ophthalmologic evaluation at regular intervals and for new or worsening visual disturbances, and to follow new or persistent ophthalmologic findings. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)].

5.4 Interstitial Lung Disease

In patients with BRAF mutation-positive melanoma receiving MEKTOVI with encorafenib (n=690), 2 patients (0.3%) developed interstitial lung disease (ILD), including pneumonitis.

Assess new or progressive unexplained pulmonary symptoms or findings for possible ILD. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)].

5.5 Hepatotoxicity

Hepatotoxicity can occur when MEKTOVI is administered in combination with encorafenib. In COLUMBUS, the incidence of Grade 3 or 4 increases in liver function laboratory tests in patients receiving MEKTOVI in combination with encorafenib was 6% for alanine aminotransferase (ALT), 2.6% for aspartate aminotransferase (AST), and 0.5% for alkaline phosphatase. No patient experienced Grade 3 or 4 serum bilirubin elevation.

Monitor liver laboratory tests before initiation of MEKTOVI, monthly during treatment, and as clinically indicated. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)].

5.6 Rhabdomyolysis

Rhabdomyolysis can occur when MEKTOVI is administered in combination with encorafenib. In COLUMBUS, elevation of laboratory values of serum CPK occurred in 58% of patients treated with MEKTOVI in combination with encorafenib. In patients with BRAF mutation-positive melanoma receiving MEKTOVI with encorafenib (n=690), rhabdomyolysis was reported in 1 patient (0.1%).

Monitor CPK and creatinine levels prior to initiating MEKTOVI, periodically during treatment, and as clinically indicated. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)].

5.7 Hemorrhage

Hemorrhage can occur when MEKTOVI is administered in combination with encorafenib. In COLUMBUS, hemorrhage occurred in 19% of patients receiving MEKTOVI in combination with encorafenib. Grade 3 or greater hemorrhage occurred in 3.2% of patients. The most frequent hemorrhagic events were gastrointestinal, including rectal hemorrhage (4.2%), hematochezia (3.1%), and hemorrhoidal hemorrhage (1%). Fatal intracranial hemorrhage in the setting of new or progressive brain metastases occurred in 1.6% of patients.

Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)].

5.8 Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, MEKTOVI can cause fetal harm when administered to a pregnant woman. Binimetinib was embryotoxic and abortifacient when administered to rabbits during the period of organogenesis at doses greater than or equal to those resulting in exposures approximately 5 times the human exposure at the recommended clinical dose of 45 mg twice daily.

Advise women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with MEKTOVI and for at least 30 days after the final dose [see Use in Specific Populations (8.1, 8.3)].

5.9 Risks Associated with Combination Treatment

MEKTOVI is indicated for use in combination with encorafenib. Refer to the encorafenib prescribing information for additional risk information that applies to combination use treatment.

6 ADVERSE REACTIONS

The following adverse reactions are described elsewhere in the labeling:

• Cardiomyopathy [see Warnings and Precautions (5.1)]
• Venous Thromboembolism [see Warnings and Precautions (5.2)]
• Ocular Toxicities [see Warnings and Precautions (5.3)]
• Interstitial Lung Disease [see Warnings and Precautions (5.4)]
• Hepatotoxicity [see Warnings and Precautions (5.5)]
• Rhabdomyolysis [see Warnings and Precautions (5.6)]
• Hemorrhage [see Warnings and Precautions (5.7)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described in Warnings and Precautions [see Warnings and Precautions (5)] reflect exposure of 192 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma to MEKTOVI (45 mg twice daily) in combination with encorafenib (450 mg once daily) in a randomized open-label, active-controlled trial (COLUMBUS) or, for rare events, exposure of 690 patients with BRAF V600 mutation-positive melanoma to MEKTOVI (45 mg twice daily) in combination with encorafenib at doses between 300 mg and 600 mg once daily across multiple clinical trials.

The data described below reflect exposure of 192 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma to MEKTOVI (45 mg twice daily) in combination with encorafenib (450 mg once daily) in COLUMBUS.

The COLUMBUS trial [see Clinical Studies (14)] excluded patients with a history of Gilbert's syndrome, abnormal left ventricular ejection fraction, prolonged QTc (> 480 msec), uncontrolled hypertension, and history or current evidence of retinal vein occlusion. The median duration of exposure was 11.8 months for patients treated with MEKTOVI in combination with encorafenib and 6.2 months for patients treated with vemurafenib.

The most common (≥ 25%) adverse reactions in patients receiving MEKTOVI in combination with encorafenib were fatigue, nausea, diarrhea, vomiting, and abdominal pain.

Adverse reactions leading to dose interruptions of MEKTOVI occurred in 33% of patients receiving MEKTOVI in combination with encorafenib; the most common were left ventricular dysfunction (6%) and serous retinopathy (5%). Adverse reactions leading to dose reductions of MEKTOVI occurred in 19% of patients receiving MEKTOVI in combination with encorafenib; the most common were left ventricular dysfunction (3%), serous retinopathy (3%), and colitis (2%). Five percent (5%) of patients receiving MEKTOVI in combination with encorafenib experienced an adverse reaction that resulted in permanent discontinuation of MEKTOVI. The most common adverse reactions resulting in permanent discontinuation of MEKTOVI were hemorrhage in 2% and headache in 1% of patients.

Table 3 and Table 4 present adverse drug reactions and laboratory abnormalities, respectively, identified in COLUMBUS. The COLUMBUS trial was not designed to demonstrate a statistically significant difference in adverse reaction rates for MEKTOVI in combination with encorafenib, as compared to vemurafenib, for any specific adverse reaction listed in Table 3.

Table 3: Adverse Reactions Occurring in ≥ 10% of Patients Receiving MEKTOVI in Combination with Encorafenib in COLUMBUS*

Other clinically important adverse reactions occurring in < 10% of patients who received MEKTOVI in combination with encorafenib were:

Gastrointestinal disorders: Colitis

Skin and subcutaneous tissue disorders: Panniculitis

Immune system disorders: Drug hypersensitivity

Table 4: Laboratory Abnormalities Occurring in ≥ 10% (All grades) of Patients Receiving MEKTOVI in Combination with Encorafenib in COLUMBUS*

7 DRUG INTERACTIONS

No clinically important drug interactions have been observed with MEKTOVI.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on findings from animal reproduction studies and its mechanism of action, MEKTOVI can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available clinical data on the use of MEKTOVI during pregnancy. In animal reproduction studies, oral administration of binimetinib during the period of organogenesis was embryotoxic and an abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 5 times the human exposure at the clinical dose of 45 mg twice daily (see Data). Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

In reproductive toxicity studies, administration of binimetinib to rats during the period of organogenesis resulted in maternal toxicity, decreased fetal weights and increased variations in ossification at doses ≥ 30 mg/kg/day (approximately 37 times the human exposure based on AUC at the recommended clinical dose of 45 mg twice daily). In pregnant rabbits, administration of binimetinib during the period of organogenesis resulted in maternal toxicity, decreased fetal body weights, an increase in malformations, and increased post-implantation loss, including total loss of pregnancy at doses ≥ 10 mg/kg/day (approximately 5 times the human exposure based on AUC at the recommended clinical dose of 45 mg twice daily). There was a significant increase in fetal ventricular septal defects and pulmonary trunk alterations at 20 mg/kg/day of binimetinib (less than 8 times the human exposure at the recommended clinical dose of 45 mg twice daily).

8.2 Lactation

Risk Summary

There are no data on the presence of binimetinib or its active metabolite in human milk, or the effects of binimetinib on the breastfed infant, or on milk production. Because of the potential for serious adverse reactions from MEKTOVI in breastfed infants, advise women not to breastfeed during treatment with MEKTOVI and for 3 days after the final dose.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating MEKTOVI [see Use in Specific Populations (8.1)].

Contraception

MEKTOVI can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Females

Advise females of reproductive potential to use effective contraception during treatment with MEKTOVI and for at least 30 days after the final dose.

8.4 Pediatric Use

The safety and effectiveness of MEKTOVI have not been established in pediatric patients.

8.5 Geriatric Use

Of the 690 patients with BRAF mutation-positive melanoma who received MEKTOVI (45 mg twice daily) in combination with encorafenib at doses between 300 mg and 600 mg once daily across multiple clinical trials, 20% were aged 65 to 74 years and 8% were aged 75 years and older. No overall differences in the safety or effectiveness of MEKTOVI plus encorafenib were observed in elderly patients as compared to younger patients [see Clinical Pharmacology (12.3)].

8.6 Hepatic Impairment

Binimetinib concentrations may increase in patients with moderate or severe hepatic impairment. Dose adjustment for MEKTOVI is not recommended in patients with mild hepatic impairment (total bilirubin > 1 and ≤ 1.5 × ULN and any AST or total bilirubin ≤ ULN and AST > ULN). Reduce the dose of MEKTOVI for patients with moderate (total bilirubin > 1.5 and ≤ 3 × ULN and any AST) or severe (total bilirubin levels > 3 × ULN and any AST) hepatic impairment [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

10 OVERDOSAGE

Since binimetinib is 97% bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with MEKTOVI.

11 DESCRIPTION

Binimetinib is a kinase inhibitor. The chemical name is 5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide. The molecular formula is C17H15BrF2N4O3 and the molecular weight is 441.2 daltons. The chemical structure of binimetinib is shown below:

Binimetinib is a white to slightly yellow powder. In aqueous media, binimetinib is slightly soluble at pH 1, very slightly soluble at pH 2, and practically insoluble at pH 4.5 and higher.

MEKTOVI (binimetinib) tablets for oral use contain 15 mg of binimetinib with the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate (vegetable source), and colloidal silicon dioxide. The coating contains polyvinyl alcohol, polyethylene glycol, titanium dioxide, talc, ferric oxide yellow, and ferrosoferric oxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Binimetinib is a reversible inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activity. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway. In vitro, binimetinib inhibited extracellular signal-related kinase (ERK) phosphorylation in cell-free assays as well as viability and MEK-dependent phosphorylation of BRAF-mutant human melanoma cell lines. Binimetinib also inhibited in vivo ERK phosphorylation and tumor growth in BRAF-mutant murine xenograft models.

Binimetinib and encorafenib target two different kinases in the RAS/RAF/MEK/ERK pathway. Compared to either drug alone, coadministration of encorafenib and binimetinib resulted in greater anti-proliferative activity in vitro in BRAF mutation-positive cell lines and greater anti-tumor activity with respect to tumor growth inhibition in BRAF V600E mutant human melanoma xenograft studies in mice. Additionally, the combination of binimetinib and encorafenib delayed the emergence of resistance in BRAF V600E mutant human melanoma xenografts in mice compared to either drug alone.

12.2 Pharmacodynamics

Cardiac Electrophysiology

Following MEKTOVI 45 mg twice daily, no clinically meaningful QT prolongation was observed.

12.3 Pharmacokinetics

The pharmacokinetics of binimetinib was studied in healthy subjects and patients with solid tumors. After twice-daily dosing, the accumulation is 1.5-fold and the coefficient of variation (CV%) of the area under the concentration-time curve (AUC) is < 40% at steady state. The systemic exposure of binimetinib is approximately dose proportional.

Absorption

After oral administration, at least 50% of the binimetinib dose was absorbed with a median time to maximum concentration (Tmax) of 1.6 hours.

Effect of Food

The administration of a single dose of MEKTOVI 45 mg with a high-fat, high-calorie meal (consisting of approximately 150 calories from protein, 350 calories from carbohydrate, and 500 calories from fat) in healthy subjects had no effect on binimetinib exposure.

Distribution

Binimetinib is 97% bound to human plasma proteins and the blood-to-plasma ratio is 0.72. The geometric mean (CV%) of apparent volume of distribution of binimetinib is 92 L (45%).

Elimination

The mean (CV%) terminal half-life (t1/2) of binimetinib is 3.5 hours (28.5%) and apparent clearance (CL/F) is 20.2 L/h (24%).

Metabolism

The primary metabolic pathway is glucuronidation with UGT1A1 contributing up to 61% of the binimetinib metabolism. Other pathways of binimetinib metabolism include N-dealkylation, amide hydrolysis, and loss of ethane-diol from the side chain. The active metabolite M3 produced by CYP1A2 and CYP2C19 represents 8.6% of the binimetinib exposure. Following a single oral dose of 45 mg radiolabeled binimetinib, approximately 60% of the circulating radioactivity AUC in plasma was attributable to binimetinib.

Excretion

Following a single oral dose of 45 mg radiolabeled binimetinib in healthy subjects, 62% (32% unchanged) of the administered dose was recovered in the feces while 31% (6.5% unchanged) was recovered in the urine.

Specific Populations

Age (20 to 94 years), sex, or body weight do not have a clinically important effect on the systemic exposure of binimetinib. The effect of race or ethnicity on the pharmacokinetics of binimetinib is unknown.

Hepatic Impairment: No clinically meaningful changes in binimetinib exposure (AUC and Cmax) were observed in subjects with mild hepatic impairment (total bilirubin > 1 and ≤ 1.5 × ULN and any AST or total bilirubin ≤ ULN and AST > ULN) as compared to subjects with normal liver function (total bilirubin ≤ ULN and AST ≤ ULN). A 2-fold increase in AUC was observed in subjects with moderate (total bilirubin > 1.5 and ≤ 3 × ULN and any AST) or severe (total bilirubin levels > 3 × ULN and any AST) hepatic impairment [see Dosage and Administration (2.4)].

Renal Impairment: In subjects with severe renal impairment (eGFR ≤ 29 mL/min/1.73 m2), no clinically important changes in binimetinib exposure were observed as compared to subjects with normal renal function.

Drug Interaction Studies

Clinical Studies

Effect of UGT1A1 Inducers or Inhibitors on Binimetinib: UGT1A1 genotype and smoking (UGT1A1 inducer) do not have a clinically important effect on binimetinib exposure. Simulations predict similar Cmax of binimetinib 45 mg in the presence or absence of atazanavir 400 mg (UGT1A1 inhibitor).

No differences in binimetinib exposure have been observed when MEKTOVI is coadministered with encorafenib.

Effect of Binimetinib on CYP Substrates: Binimetinib did not alter the exposure of a sensitive CYP3A4 substrate (midazolam).

Effect of Acid Reducing Agents on Binimetinib: The extent of binimetinib exposure (AUC) was not altered in the presence of a gastric acid reducing agent (rabeprazole).

In Vitro Studies

Effect of Binimetinib on CYP Substrates: Binimetinib is not a time-dependent inhibitor of CYP1A2, CYP2C9, CYP2D6 or CYP3A.

Effect of Transporters on Binimetinib: Binimetinib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Binimetinib is not a substrate of organic anion transporting polypeptide (OATP1B1, OATP1B3, OATP2B1) or organic cation transporter 1 (OCT1).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies with binimetinib have not been conducted. Binimetinib was not genotoxic in studies evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells, or micronuclei in bone marrow of rats.

No dedicated fertility studies have been conducted with binimetinib in animals. In general toxicology studies in rats and monkeys, there were no remarkable findings in male or female reproductive organs.

14 CLINICAL STUDIES

MEKTOVI in combination with encorafenib was evaluated in a randomized, active-controlled, open-label, multicenter trial (COLUMBUS; NCT01909453). Eligible patients were required to have BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma, as detected using the bioMerieux THxID™BRAF assay. Patients were permitted to have received immunotherapy in the adjuvant setting and one prior line of immunotherapy for unresectable locally advanced or metastatic disease. Prior use of BRAF inhibitors or MEK inhibitors was prohibited. Randomization was stratified by American Joint Committee on Cancer (AJCC) Stage (IIIB, IIIC, IVM1a or IVM1b, versus IVM1c), Eastern Cooperative Oncology Group (ECOG) performance status (0 versus 1), and prior immunotherapy for unresectable or metastatic disease (yes versus no).

Patients were randomized (1:1:1) to receive MEKTOVI 45 mg twice daily in combination with encorafenib 450 mg once daily (MEKTOVI in combination with encorafenib), encorafenib 300 mg once daily, or vemurafenib 960 mg twice daily. Treatment continued until disease progression or unacceptable toxicity. Only the results of the approved dosing (MEKTOVI 45 mg in combination with encorafenib 450 mg) are described below.

The major efficacy outcome measure was progression-free survival (PFS), as assessed by a blinded independent central review, to compare MEKTOVI in combination with encorafenib with vemurafenib. Additional efficacy measures included overall survival (OS), as well as objective response rate (ORR) and duration of response (DoR) which were assessed by central review.

A total of 577 patients were randomized, 192 to the MEKTOVI in combination with encorafenib arm, 194 to the encorafenib arm, and 191 to the vemurafenib arm. Of the 383 patients randomized to either the MEKTOVI in combination with encorafenib or the vemurafenib arms, the median age was 56 years (20 to 89 years), 59% were male, 91% were White, and 72% had baseline ECOG performance status of 0. Ninety-five percent (95%) had metastatic disease, 65% were Stage IVM1c, and 4% received prior CTLA-4, PD-1, or PD-L1 directed antibodies. Twenty-eight percent (28%) had elevated baseline serum lactate dehydrogenase (LDH), 45% had ≥ 3 organs with tumor involvement at baseline, and 3% had brain metastases. Based on centralized testing, 100% of patients' tumors tested positive for BRAF mutations; BRAF V600E (88%), BRAF V600K (11%), or both (< 1%).

MEKTOVI in combination with encorafenib demonstrated a statistically significant improvement in PFS compared to vemurafenib. Efficacy results are summarized in Table 5 and Figure 1.

Table 5: Efficacy Results for COLUMBUS

Figure 1: Kaplan-Meier Curves for Progression-Free Survival in COLUMBUS

16 HOW SUPPLIED/STORAGE AND HANDLING

MEKTOVI (binimetinib) is supplied as 15 mg yellow/dark yellow, unscored biconvex oval film-coated tablets debossed with a stylized "A" on one side and "15" on the other side, available in bottles of 180 tablets (NDC 70255-010-02).

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Inform patients of the following:

Cardiomyopathy

Advise patients to report any symptoms of heart failure to their healthcare provider [see Warnings and Precautions (5.1)].

Venous Thrombosis

Advise patients to contact their healthcare provider if they experience symptoms of venous thrombosis or pulmonary embolism. Advise patients to seek medical attention for sudden onset of difficulty breathing, leg pain, or swelling [see Warnings and Precautions (5.2)].

Ocular Toxicities

Advise patients to contact their healthcare provider if they experience any changes in their vision [see Warnings and Precautions (5.3)].

Interstitial Lung Disease

Advise patients to contact their healthcare provider if they experience any new or worsening respiratory symptoms including cough or dyspnea [see Warnings and Precautions (5.4)].

Hepatotoxicity

Advise patients that serial testing of serum liver tests (ALT, AST, bilirubin) is recommended during treatment with MEKTOVI. Instruct patients to report symptoms of liver dysfunction including jaundice, dark urine, nausea, vomiting, loss of appetite, fatigue, bruising, or bleeding [see Warnings and Precautions (5.5)].

Rhabdomyolysis

Advise patients to contact their healthcare provider as soon as possible if they experience unusual or new onset weakness, myalgia, or darkened urine [see Warnings and Precautions (5.6)].

Hemorrhage

Advise patients to notify their healthcare provider if they experience symptoms suggestive of hemorrhage, such as unusual bleeding [see Warnings and Precautions (5.7)].

Females and Males of Reproductive Potential

Embryo-Fetal Toxicity: Advise females with reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with MEKTOVI and for 30 days after the final dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with MEKTOVI [see Warnings and Precautions (5.8), Use in Specific Populations (8.1)].

Lactation: Advise women not to breastfeed during treatment with MEKTOVI and for 3 days after the final dose [see Use in Specific Populations (8.2)].

Distributed by:
Array BioPharma Inc.
3200 Walnut Street
Boulder, CO 80301

© 2018 Array BioPharma Inc. All rights reserved.
MEKTOVI® is a registered trademark of Array BioPharma Inc. in the United States and various other countries.
Patented. See www.arraybiopharma.com/patents

PRINCIPAL DISPLAY PANEL - 15 mg Tablet Bottle Carton

NDC 70255-010-02

MEKTOVI®
(binimetinib) tablets

15 mg

Rx only

180 Tablets

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