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Synribo(omacetaxine mepesuccinate)使用说明书2012年10月第一版

批准日期：10月 26，2012；公司：Teva Pharmaceuticals

FDA药物评价和研究中心的血液学和肿瘤室主任Richard Pazdur，M.D.说：“今天的批准为FDA批准的其他CML的慢些或加速期药物对耐药或不能耐受的患者提供一种新治疗选择，”“Synribo是在过去两个月被批准治疗CML的第二个药物。”


Synribo是在美国FDA加速批准计划下被批准的，这个计划允许监督管理局根据临床数据显示药物对一个替代性终点有理由可能预测对患者有效益而临床批准一个药物治疗一种严重疾病。这个计划更早提供患者有前途新药而公司进行附加临床研究验证使用该药物的临床效益和安全。Synribo还接受FDA的孤儿(罕见)药物指定因为意向治疗一种罕见疾病或条件。

处方资料重点
这些重点不包括安全和有效使用SYNRIBO所需所有资料。请参阅下文为SYNRIBO的完整处方资料
注射用SYNRIBO™(omacetaxine mepesuccinate)，为皮下使用
美国初次批准：2012
 
适应症和用途
注射用SYNRIBO适用于为治疗有慢性或加速期慢性粒性白血病(CML)与对两种或更多酪氨酸激酶抑制剂(TKI)耐药性和/或不能耐受的成年患者。这个适应症是根据反应率。没有试验证明用SYNRIBO改善疾病相关症状或增加生存。(1)

剂型和给药方法
● 诱导剂量：1.25 mg/m2通过皮下注射给药每天2次共28-天疗程的连续14天。(2.1)
● 维持剂量：1.25 mg/m2通过皮下注射给药每天2次共28-天疗程的连续7天。(2.2)
● 对毒性需要调整剂量。(2.3)

剂型和规格
单次使用小瓶含3.5 mg的omacetaxine mepesuccinate为冻干粉。(3)

禁忌症
无。

警告和注意事项¬
● 骨髓抑制：严重和致死性血小板减少，中性粒细胞减低和贫血。频繁监视血液学参数。(2.3，5.1)
● 出血：严重血小板减少和出血风险增加。致命性脑出血和严重，非致命性胃肠道出血。(5.1，5.2)
● 高血糖：葡萄糖不能耐受和高血糖包括高渗性非酮性高血糖。(5.3)
● 胚胎胎儿毒性：可能致胎儿危害。建议有生育能力妇女避免妊娠。(5.4，8.1)

不良反应
CML-慢性期和加速期：最常见不良反应(频数 ≥20%)：血小板减少，贫血，中性粒细胞减低，腹泻，恶心，疲乏，虚弱，注射部位反应，发热，感染，淋巴细胞减少。(6.1)
为报告怀疑不良反应，联系Teva Pharmaceutical USA，Inc.电话1-800-896-5855或FDA电话1-800-FDA-1088或www.fda.gov/medwatch.

完整处方资料

1 适应症和用途
SYNRIBO适用于治疗对两种或更多酪氨酸激酶抑制剂(TKI)耐药和/或不能耐受慢性或加速期慢性粒性白血病(CML)成年患者。这个适应症是根据反应率。没有用SYNRIBO试验验证疾病相关症状或增加生存。

2 剂型和给药方法
2.1 诱导方案
对诱导的推荐开始方案是1.25 mg/m2皮下给药每天2次每28天共连续14天，跨越一个28天疗程。疗程应每28天重复直至患者实现血液学反应。
 
2.2 维持给药
推荐的维持是1.25 mg/m2皮下给药每天2次每28天共连续7天，跨越一个28天疗程。只要患者临床上从治疗获益应继续治疗。

2.3 剂量调整和修改
血液学毒性：对血液学毒性(如中性粒细胞减低，血小板减少)SYNRIBO治疗疗程可能被延后和/或疗程期间减少给药的天数。[见警告和注意事项(5.1)]
诱导和初始维持疗程应每周进行完全血细胞计数(CBCs)。初始维持疗程后，当临床上指示时每两周监视CBCs。如疗程期间患者经受4级中性粒细胞减低(嗜中性绝对计数(ANC)低于0.5 × 109/L)或3级血小板减少(血小板计数低于50 × 109/L)，延后开始下一疗程直至中性粒细胞计数ANC大于或等于1.0 × 109/L和血小板计数大于或等于50 × 109/L。还有，对下一疗程，减低给药天数2天(如至12或5天)。
非-血液学毒性：对症处理其他临床意义的非血液学毒性。中断和/或延后SYNRIBO直至毒性解决。

2.4 准备和给药注意事项
应在医疗保健设施处准备SYNRIBO和由卫生保健专业人员给药。Omacetaxine mepesuccinate是一种抗肿瘤产品。遵循专门处置和遗弃方法步骤。
皮下注射前用1 mL的0.9%氯化钠注射液，USP，重建SYNRIBO。加入稀释液后，轻轻旋转直至得到透明溶液。冻干粉应在短于１分钟内完全溶解。得到溶液将含3.5 mg/mL SYNRIBO。
肠道外药物产品只要溶液和容器允许应肉眼观察颗粒物质和变色。避免接触皮肤。如SYNRIBO接触皮肤，用肥皂和水立即和彻底洗涤受影响面积。
当贮存在室温重建SYNRIBO在12小时内使用和如贮存在2°C至8 °C(36oF至46oF)在重建的24小时内。避光保护重建溶液。给药后，应适当地丢弃任何未使用溶液1。

3 剂型和规格
SYNRIBO注射用含3.5 mg omacetaxine mepesuccinate；为在单次使用小瓶中的无菌，无防腐剂，白色至灰白色冻干粉。

4 禁忌症
无。.

5 警告和注意事项
5.1 骨髓抑制
在用SYNRIBO无对照试验，有慢性期和加速期CML患者分别经受NCI CTC(版本3.0)3或4级血小板减少(85%，88%)，中性粒细胞减低(81%，71%)，和贫血(62%，80%)。在安全性人群(N=163)中3%患者发生骨髓抑制相关死亡。中性粒细胞减低患者是处在感染风险增加，和应频繁监视和如有感染或发热症状劝告联系医生。
在诱导和初始维持疗程和维持疗程后期当临床上指示时每周监视完全血细胞计数。在临床试验中骨髓抑制一般是可逆的和通常用延后下一疗程处理疗程和/或减少用SYNRIBO治疗天数[见剂型和给药方法(2.3)和不良反应(6.1)]

5.2 出血
SYNRIBO引起严重血小板减少增加出血风险。在临床试验中有CP和AP CML患者，观察到3和4级血小板减少发生率高(分别85%和88%)。在安全性人群中用SYNRIBO治疗患者2%发生来自脑出血死亡。在安全性人群2%患者发生严重，非致命性，胃肠道出血。大多数出血事件伴随严重血小板减少。
建议监视血小板计数作为全血细胞CBC监视的一部分[见警告和注意事项(5.1)]。当血小板计数低于50,000/μL避免抗凝剂，阿司匹林，和非甾体抗炎药(NSAIDs)因可能增加出血风险。

5.3 高血糖
SYNRIBO可能诱发葡萄糖不能耐受。在安全性人群中11%患者报道3或4级高血糖。在安全性人群中用SYNRIBO治疗患者发生1例高渗性非酮性高血糖。频繁监视血葡萄糖水平，尤其是糖尿病或糖尿病风险因子患者。避免在糖尿病控制不佳患者使用SYNRIBO直至确定已良好控制血糖。

5.4 胚胎胎儿毒性
当SYNRIBO给予妊娠妇女可能致胎儿危害。在动物中Omacetaxine mepesuccinate引起胚胎-胎儿死亡。有生育能力妇女当正在用SYNRIBO时应避免成为妊娠。在妊娠妇女中没有SYNRIBO的适当和对照良好研究。如此药在妊娠期间使用，或当接受此药时患者成为妊娠，应忠告患者对胎儿潜在危害[见在特殊人群中使用(8.1)]。

6 不良反应
在临床试验中伴随SYNRIBO以下严重不良反应和在说明书的其他节中更详细探讨：
● 骨髓抑制[见警告和注意事项(5.1)]
● 出血[见警告和注意事项(5.2)]
● 高血糖[见警告和注意事项(5.3)]
因为临床试验是在广泛不同情况下进行的，临床试验观察到不良反应率不能与另一种药临床试验发生率直接比较而且可能不反映实践中观察到的发生率。
从3项临床试验得到对SYNRIBO的安全性数据，其中总共纳入163例酪氨酸酶抑制TKI 耐药和/或不能耐受的慢性期(N=108)和加速期(N=55)CML成年患者。所有患者用初始诱导治疗，包括剂量1.25 mg/m2皮下给药每天2次每28天共连续14天(诱导疗程)。然后有反应患者用相同剂量治疗和一个每天2次方案每28天共连续7天(维持疗程)。

6.1 临床试验经验
慢性期CML
108例慢性期CML患者中位暴露时间为7.4个月(范围0至43个月)。暴露的中位总疗程为6个月(范围1至41)，和试验期间输送中位总剂量为131 mg/m2(范围1.2至678)。慢性期CML患者中，治疗疗程1期间87%接受14天。疗程2和3，接受14天治疗患者的百分率分别减低至42%和16%。其中91例患者至少接受2个疗程治疗，试验期间79例(87%)至少延迟1个疗程。当更多患者接受诱导疗程最长的疗程延迟中位天数对疗程2(17天)和疗程3(25天)。

99%的慢性期CML患者报道不良反应。总共18%患者因不良反应导致撤药。导致终止最频发生不良反应为全细胞减少，血小板减少，和丙氨酸转移酶增加(各2%)。总共87%患者至少报道1次 3级或4级治疗出现不良反应(表1)。

对51%患者报道严重不良反应。报道的严重不良反应至少5%患者是骨髓衰竭和血小板减少(各10%)，和发热性中性粒细胞减低(6%)。8%患者报道感染严重不良反应。
在5例(5%)CP CML患者研究时发生死亡。两例患者死于脑出血，1例由于多器官衰竭，1例由于疾病的进展,和1例原因不明。
加速期CML
暴露的中位总疗程为2(范围1至29)，和试验期间输送中位总剂量为70 mg/m2。中位暴露时间对55例加速期CML患者为1.9个月(范围0至30个月)。其中加速期CML患者，疗程1期间86%接受14天治疗。疗程2和3，接受14天治疗患者的百分率分别减低至55%和44%。其中40例患者至少接受2个疗程治疗，延迟试验期间27例(68%)至少1个疗程。延迟疗程最大中位天数对疗程3(31天)和疗程8(36天)。
无论研究者归属对加速期CML患者报道不良反应100%。总共33%患者有不良反应导致撤药。导致撤药最频发生不良反应是白细胞增多(6%)，和血小板减少(4%). 总共84%患者报道至少1次3级或4级治疗出现的不良反应(表2)。

 60%患者报道严重不良反应。报道的严重不良反应至少5%患者是发热性中性粒细胞减低(18%)，血小板减少(9%)，贫血(7%)，腹泻和抽搐(各6%)。对11%患者报道的严重不良反应是感染。在研究中5例(9%) AP CML患者发生死亡。两例患者死于脑出血和3例由于疾病进展。
在慢性和加速期CML实验室异常
表3中描述在有慢性和加速期CML患者中报道的3/4级实验室异常。所有用SYNRIBO治疗患者发生骨髓抑制[见警告和注意事项(5.1)]。5例慢性期CML和4患者加速期CML患者由于全细胞减少，血小板减少，发热性中性粒细胞减低，或骨髓坏死永远终止SYNRIBO。在安全性人群报道1例高渗性非酮性高血糖事件和在文献中报道1相似病例。两例慢性期CML患者由于转氨酶升高永远终止SYNRIBO。

6.2 来自安全性人群另外数据
在慢性期和加速期CML患者SYNRIBO临床研究报道有频数1%至小于10%患者以下不良反应。每一类中，不良反应是根据频数排列。
心脏疾病：心动过速，心悸，急性冠状动脉综合症，心绞痛，心律不齐，心动过缓，室性期外收缩。
耳和迷路疾病：耳痛，耳出血，耳鸣。
眼疾病：白内障，视力模糊，结膜出血，干眼，流泪增加，结膜炎，复视，眼痛，眼睑水肿。
胃肠道疾病：口炎，口腔溃疡，腹胀，消化不良，胃食道回流病，牙龈出血，阿弗他口炎，口干，痔疮，胃炎，胃肠道出血，黑便，口出血，口痛，肛门裂，吞咽困难，龈痛，齿龈炎。
一般疾病和给药部位情况：粘膜炎症，疼痛，胸痛，高温，流感样不适，导管部位痛，全身水肿，不适。
免疫系统疾病：超敏性。
损伤，中毒和手术并发症：挫伤，输血反应。
代谢和营养疾病：减低食欲，糖尿病，痛风，脱水。
肌肉和结缔组织疾病：骨痛，肌痛，肌肉软弱，肌肉痉挛，肌肉骨骼胸痛，肌肉骨骼痛，肌肉骨骼僵硬，肌肉骨骼不适。
神经系统疾病：眩晕，脑出血，感觉异常，抽搐，感觉迟钝，昏睡，坐骨神经痛，烫觉，味觉障碍，震颤。
精神疾病：焦虑，抑郁，激动，精神混乱状态，精神状态变化。
肾和泌尿疾病：排尿困难。
呼吸，胸和纵隔疾病：咽喉痛，鼻充血，发声困难，有痰咳嗽，罗音，流鼻涕，咯血，鼻窦充血。
皮肤和皮下组织疾病：红斑，瘙痒，干皮肤，瘀斑，多汗症，夜汗，出血斑，紫癜，皮肤损伤，皮肤溃疡，红斑性皮疹，丘皮疹，皮肤去角质，皮肤色素沉着。
血管疾病：血肿，高血压，潮热，低血压。

7 药物相互作用
根据来自体外用SYNRIBO药物相互作用研究发现，无必要临床临床药物相互作用试验。[见临床药理学(12.3)]

8 特殊人群中使用
8.1 妊娠
妊娠类别D[见警告和注意事项(5.4)]
根据其作用机制和来自动物研究发现，当给予妊娠妇女SYNRIBO可能致胎儿危害。如妊娠期间使用本药，或如服用此药时患者成为妊娠，应忠告患者对胎儿潜在危害。
在一项胚胎-胎儿发育研究，在器官形成期时妊娠小鼠被皮下给予omacetaxine mepesuccinate剂量0.21或0.41 mg/kg/day。药物-相关不良作用包括胚胎死亡，未骨化骨/减低骨化增加和减低胎儿体重。胎儿毒性发生在剂量0.41 mg/kg(1.23 mg/m2)按照体表面积为人每天推荐剂量的约一半。

8.3 哺乳母亲
不知道omacetaxine mepesuccinate是否排泄在人乳汁中。因为许多药物排泄在乳汁和因为哺乳婴儿严重不良反应的潜能，应做出决策是否继续哺乳或终止药物，考虑药物对母亲的重要性。

8.4 儿童使用
未确定SYNRIBO在儿童患者中安全性和有效性。

8.5 老年人使用
在慢性和加速期CML中疗效人群中23(30%)和16(46%)患者是 ≥65岁。对<65岁和≥65岁年龄亚组，亚组间有差异，较轻CP CML患者与较老患者比较主要细胞遗传学反应(MCyRs)有较高率(分别23%相比9%)和较老AP CML患者d与较年轻患者比较主要血液学反应(MaHRs)有较高率(分别31%相比0%)。≥65岁患者更可能经受毒性，最显著为血液学毒性。  

8.6 肾受损
未进行正式研究评估肾受损对omacetaxine mepesuccinate的药代动力学的影响。

8.7 肝受损
未进行正式研究评估肝受损对omacetaxine mepesuccinate的药代动力学的影响。

8.8 性别的效应
在慢性期CML人群疗效分析包括76例患者，其中47例(62%)患者为男性和29例(38%)为女性。对慢性期CML患者，男性MCyR率高于妇女(分别21%相比14%)。注意到在男性和妇女慢性期CML中omacetaxine mepesuccinate的安全性图形有差别。虽然各组患者数量小阻止确定性评估。在加速期亚组患者数不适当得出性别对疗效影响的结论。

10 药物过量
在临床计划中1例患者接受过量2.5 mg/m2每天2次共5天。患者出现胃肠道功能紊乱，牙龈出血，脱发，和4级血小板减少和中性粒细胞减低。当SYNRIBO治疗被暂时中断胃肠道功能紊和出血综合征解决，和嗜中性值返回正常范围内。脱发和血小板减少(1级)改善，和SYNRIBO重新开始。

11 一般描述
SYNRIBO含活性成分omacetaxine mepesuccinate，一种三尖杉碱酯[cephalotaxine ester]。它是一种蛋白合成抑制剂。Omacetaxine mepesuccinate是通过从粗榧碱[cephalotaxine]半-合成过程制备，前者从三尖杉藻[Cephalotaxus sp]叶中萃取。Omacetaxine mepesuccinate的化学名是粗榧碱，4-methyl(2R)-hydroxyl-2-(4-hydroxyl-4-methylpentyl) butanedioate(ester)。
Omacetaxine mepesuccinate的结构式如下：
 
分子式C29H39NO9有分子量545.6 g/mol。SYNRIBO注射用是无菌，无防腐剂，白色至灰白色，冻干粉在单次使用小瓶中。各小瓶含3.5 mg omacetaxine mepesuccinate和甘露醇。SYNRIBO意向用1.0 mL的0.9%氯化钠注射液，USP重建后皮下给药。重建溶液的pH在5.5和7.0间。

12 临床药理学
12.1 作用机制
Omacetaxine mepesuccinate的作用机制尚未完全阐明但包括蛋白质合成的抑制及其独立直接cr-Abl结合作用。Omacetaxine mepesuccinate结合至来自一株古细菌[archaeabacteria]核糖体大亚单位[large ribosomal subunit]的中心肽基转移酶[peptidyl-transferase]中裂缝一个位点。在体外，omacetaxine mepesuccinate减低Bcr-Abl癌蛋白和Mcl-1的蛋白质水平，是抗凋亡Bcl-2一个家族成员。Omacetaxine mepesuccinate在野生型和T315I突变Bcr-Abl CML小鼠模型中显示活性。

12.3 药代动力学
不知道omacetaxine mepesuccinate的剂量正比例性。观察到在首次给药和稳态间omacetaxine mepesuccinate的全身暴露增加90%。
吸收 未曾测定omacetaxine mepesuccinate的绝对生物利用度。Omacetaxine mepesuccinate是从皮下给药吸收，和约30分钟后实现最大浓度。
分布 皮下给药1.25 mg/m2每天2次共11天Omacetaxine mepesuccinate的稳态(均数 ± SD)分布容积约为141 ± 93.4 L。Omacetaxine mepesuccinate的血浆蛋白结合是小于或等于50%.
代谢 在体外Omacetaxine mepesuccinate是主要通过血浆酯酶水解为4′-DMHHT与小量肝微粒体氧化和/或酯酶-介导代谢。
消除 不知道omacetaxine mepesuccinate的主要消除途径。在尿中排泄的未变化omacetaxine mepesuccinate平均百分率小于15%。皮下给药后omacetaxine mepesuccinate的半衰期为约6小时。
药物相互作用细胞色素P450酶(CYPs)：在体外，Omacetaxine mepesuccinate不是CYP450酶的底物。临床上期望Omacetaxine mepesuccinate和4′-DMHHT浓度在体外不抑制主要CYPs。未测定omacetaxine mepesuccinate或4′-DMHHT诱导CYP450酶的潜能。
转运蛋白系统：在体外Omacetaxine mepesuccinate是P-糖蛋白(P-gp)的底物。临床上可期望的Omacetaxine mepesuccinate和4′-DMHHT浓度体外不抑制P-gp介导的洛哌丁胺[loperamide]的流出。

12.6 评估QT延长的风险
在21例接受omacetaxine mepesuccinate 1.25 mg/m2 BID共14连续天治疗患者的一项无对照药代动力学研究中未报道QTcF > 480 ms或ΔQTcF > 60 ms。对omacetaxine mepesuccinate或4’-DMHHT没有浓度-依赖性QTc的增加的证据。 虽然对QTc平均效应为4.2 ms(95% CI上限：9.5 ms)，由于缺乏安慰剂和阳性对照QTc效应小于10 ms无法验证。

13 非临床毒理学
13.1 癌发生，突变发生，生育能力受损
未曾用omacetaxine mepesuccinate进行致癌性研究。
在中国仓鼠卵巢(CHO)细胞在体外染色体畸变测试系统Omacetaxine mepesuccinate是遗传毒性，但不是致突变性当在一种体外细菌细胞试验(Ames试验)，和用一种体内小鼠微核试验不诱发遗传损伤。
SYNRIBO可能损害雄性生育能力。在小鼠中研究显示对雄性生殖器官不良效应。高剂量组(2.33 mg/kg/day 减低至1.67 mg/kg/day；7至5 mg/m2/day)在6个月期间皮下注射omacetaxine mepesuccinate共6个周期后，报道双侧睾丸中生精小管上皮细胞退行性变性和在附睾中精子减少/无精子。根据体表面积，在小鼠中所用该剂量约临床剂量(2.5 mg/m2/day)的2至3倍。

14 临床研究
用来自两项试验的一个CML成年患者合并队列评价SYNRIBO的疗效。合并队列包括患者曾接受2种或更多被批准酪氨酸激酶抑制和曾，最小，记录的对达沙替尼[dasatinib]和/或尼洛替尼[nilotinib]耐药或不能耐受的证据。耐药性被定义为以下之一：无完全血液学反应(CHR)共12周(是否丢失或从来未实现)；或至24周无细胞遗传学反应(即，100% Ph阳性[Ph+])(是否丢失或从来未实现)；或至52周无重大细胞遗传学反应(MCyR) (即，≥35% Ph+)(是否丢失或从来未实现)；或进展性白细胞增多症。不能耐受被定义为以下之一：1) 3-4级非血液学毒性用适当干预没有解决；或2)4级血液学毒性持续7天以上；或3)对患者不能接受的任何≥ 2级毒性。排除有NYHA类别III或IV心脏病，活性缺血或其他未控制心脏情况患者。
用omacetaxine mepesuccinate在剂量1.25 mg/m2皮下给药每天2次每28天共连续14天(诱导疗程)治疗患者。反应患者然后用相同剂量和每天2次方案治疗每28天共连续7天(维持疗程)。允许患者继续接受维持治疗直至24个月。由一个独立数据监视委员会(DMC)裁决反应。

14.1 慢性期CML(CP CML)
在疗效分析中总共包括76例慢性期CML患者。人口统计指标为：中位年龄59岁，62%为男性，30%为年龄65岁或以上，80%为高加索人，5% 为非洲-美国人，4%为亚裔和4%为西班牙裔。36例(47%)患者曾用伊马替尼[imatinib]，达沙替尼,和尼洛替尼治疗失败。大多数患者既往曾接受非-酪氨酸激酶抑制剂治疗，大多数常是羟基脲[hydroxyurea](54%)，干扰素[interferon](30%)，和/或阿糖胞苷[cytarabine](29%)。
疗效终点是根据MCyR(由独立数据监视委员会DMC裁决)。

 在14例患者中平均至MCyR开始时间为3.5个月。对14例患者MCyR的中位时间为 12.5个月(Kaplan-Meier估计值)。

14.2 加速期CML(AP CML)
在疗效分析中总共包括35例有加速期CML患者。人口统计指标为：中位年龄63岁，57% 为男性，46%年龄为65岁或以上，68%为高加索人，23%为非洲每个人，3%为亚裔和3% 为西班牙裔。22/3例(63%)有加速期患者用伊马替尼，达沙替尼，和尼洛替尼治疗失败。大多数患者还曾接受既往非-酪氨酸激酶抑制剂治疗，大多数常为羟基脲(43%)，干扰素(31%)，和/或阿糖胞苷(29%)。评估疗效终点根据MCyR和MaHR(完全血液学反应[CHR]或无白血病证据[NEL])。表5中显示由独立数据监视委员会DMC对加速期患者裁决的疗效结果。

 5例患者中平均反应开始时间为2.3个月。对5例患者MaHR的中位时间为4.7个月(Kaplan-Meier估计值)。

15 参考资料
1. OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

16 如何供应/贮存和处置
16.1 如何供应
注射用SYNRIBO(omacetaxine mepesuccinate)在各别纸盒中的8 mL透明玻璃单次使用小瓶供应。每个小瓶含3.5 mg注射用SYNRIBO(omacetaxine mepesuccinate) (NDC 63459-177-14)。

16.2 贮存和处置
贮存在20oC至25ºC(68o C至77ºF)；外出允许从15ºC至30ºC(59ºF至86ºF)。用前产品避光保护保持在盒内。 Omacetaxine mepesuccinate是一种抗肿瘤产品。遵循专门处置和遗弃方法步骤1。

17 患者咨询资料
● 出血 劝告患者由于低血小板计数严重出血的可能性。指导患者立即报告任何体征或症状提示出血 (不寻常出血，容易擦伤或尿和粪中血；混乱，语言不清，或视力改变)。
● 骨髓抑制 劝告患者SYNRIBO将引起白细胞，血小板，和红细胞减低的可能性和需要监视这些参数。教导患者如发生发热或其他感染体征/症状；气短，显著疲乏，或出血联系卫生保健专业人员。
● 高血糖 劝告糖尿病患者高血糖的可能性和需要仔细监视血葡萄糖水平。控制不佳的糖尿病患者不应用omacetaxine mepesuccinate治疗直至确定良好的血糖控制。
● 妊娠和哺乳 劝告患者当妊娠妇女给予omacetaxine mepesuccinate可能致胎儿危害。劝告有生育能力妇女对胎儿潜在危害和避免成为妊娠。劝告女性当接受SYNRIBO时避免哺乳。
● 胃肠道主诉 劝告患者可能经受恶心，腹泻，腹痛，便秘，和呕吐。如这些症状持续，应寻求医疗照顾。
● 疲乏 劝告患者SYNRIBO可能引起疲劳和如经受此副作用避免驾驶任何车辆或操作任何危险工具或机械。
● 皮疹 劝告患者可能经受皮疹。劝告患者立即报告严重或恶化皮疹或发痒。•
● 脱发 劝告患者可能经受脱发。

 

Synribo

Generic Name: omacetaxine mepesuccinate
Dosage Form: injection, powder, lyophilized, for solution

Medically reviewed on June 1, 2017

Indications and Usage for Synribo

Synribo is indicated for the treatment of adult patients with chronic or accelerated phase chronic myeloid leukemia (CML) with resistance and/or intolerance to two or more tyrosine kinase inhibitors (TKI).

Synribo Dosage and AdministrationInduction Schedule

The recommended starting schedule for induction is 1.25 mg/m2 administered subcutaneously twice daily at approximately 12 hour intervals for 14 consecutive days every 28 days, over a 28-day cycle. Cycles should be repeated every 28 days until patients achieve a hematologic response

Maintenance Dosing

The recommended maintenance schedule is 1.25 mg/m2 administered subcutaneously twice daily at approximately 12 hour intervals for 7 consecutive days every 28 days, over a 28-day cycle. Treatment should continue as long as patients are clinically benefiting from therapy.

Dose Adjustments and Modifications

Hematologic Toxicity:

Synribo treatment cycles may be delayed and/or the number of days of dosing during the cycle reduced for hematologic toxicities (e.g. neutropenia, thrombocytopenia) [see Warnings and Precautions (5.1)].

Perform complete blood counts (CBCs) weekly during induction and initial maintenance cycles. After initial maintenance cycles, monitor CBCs every two weeks or as clinically indicated. If a patient experiences Grade 4 neutropenia (absolute neutrophil count (ANC) less than 0.5 x 109/L) or Grade 3 thrombocytopenia (platelet counts less than 50 x 109/L) during a cycle, delay starting the next cycle until ANC is greater than or equal to 1.0 x 109/L and platelet count is greater than or equal to 50 x 109/L. Also, for the next cycle, reduce the number of dosing days by 2 days (e.g. to 12 or 5 days).

Non-Hematologic Toxicity:

Manage other clinically significant non-hematologic toxicity symptomatically. Interrupt and/or delay Synribo until toxicity is resolved.

Reconstitution Instructions and Handling Precautions

Synribo should be prepared in a healthcare facility and must be reconstituted by a healthcare professional.

Reconstitute Synribo with one mL of 0.9% Sodium Chloride Injection, USP, prior to subcutaneous injection. After addition of the diluent, gently swirl until a clear solution is obtained. The lyophilized powder should be completely dissolved in less than one minute. The resulting solution is clear and colorless and contains 3.5 mg/mL Synribo. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Synribo does not contain antimicrobial preservatives. Therefore care must be taken to ensure that the solution for injection is not contaminated during preparation.

Synribo is a cytotoxic drug. Follow special handling and disposal procedures1. Wear protective eyewear and gloves during handling and administration of the product. Proper aseptic technique should be used. Avoid skin and eye contact. If Synribo comes into contact with skin, immediately and thoroughly wash affected area with soap and water. If contact with the eyes occurs, thoroughly flush the eyes with water.

Storage Conditions and Storage Time after Preparation of Syringes

If Synribo is not used immediately after reconstitution, follow in-use storage conditions and allowable storage times prior to use as instructed in Table 1. Do not administer Synribo outside of the storage conditions and timeframes listed in Table 1.

Table 1: Storage Conditions and Storage Time after Preparation of Syringes
Storage Conditions	Storage Time
Room temperature (20°C to 25°C [68°F to 77°F])	Use within 12 hours of reconstitution
Refrigerated (2°C to 8°C [36oF to 46oF])	Use within 6 days (144 hours) of reconstitution

Considerations for Home Administration

Before a decision is made to allow Synribo to be administered by someone other than a healthcare professional, ensure that the patient is an appropriate candidate for self-administration or for administration by a caregiver. Provide training on proper handling, storage conditions, administration, disposal, and clean-up of accidental spillage of the product. Ensure that patients receive the necessary supplies for home administration. At minimum these should include:

•

Reconstituted Synribo in syringe with a capped needle for subcutaneous injection. Syringe(s) should be filled to the patient-specific dose.

•

Protective eyewear

•

Gloves

•

An appropriate biohazard container

•

Absorbent pad(s) for placement of administration materials and for accidental spillage

•

Alcohol swabs

•

Gauze pads

•

Ice packs or cooler for transportation of reconstituted Synribo syringes

If a patient or caregiver cannot be trained for any reason, then in such patients, Synribo should be administered by a healthcare professional.

Disposal and Accidental Spillage Procedures

After administration, any unused solution should be discarded properly1. Instruct patients planning home administration on the following: do not recap or clip the used needle, and do not place used needles, syringes, vials, and other used supplies in a household trash or recycling bin. Used needles, syringes, vials, and other used supplies should be disposed of in an appropriate biohazard container.

If accidental spillage occurs, continue to use protective eyewear and gloves, wipe the spilled liquid with the absorbent pad, and wash the area with water and soap. Then, place the pad and gloves into the biohazard container and wash hands thoroughly. Return the biohazard container to the clinic or pharmacy for final disposal.

Dosage Forms and Strengths

Synribo for Injection contains 3.5 mg omacetaxine mepesuccinate; as a sterile, preservative-free, white to off-white lyophilized powder in a single-dose vial.

Contraindications

None.

Warnings and PrecautionsMyelosuppression

In uncontrolled trials with Synribo, patients with chronic phase and accelerated phase CML experienced NCI CTC (version 3.0) Grade 3 or 4 thrombocytopenia (85%, 88%), neutropenia (81%, 71%), and anemia (62%, 80%), respectively. Fatalities related to myelosuppression occurred in 3% of patients in the safety population (N=163). Patients with neutropenia are at increased risk for infections, and should be monitored frequently and advised to contact a physician if they have symptoms of infection or fever.

Monitor complete blood counts weekly during induction and initial maintenance cycles and every two weeks during later maintenance cycles, as clinically indicated. In clinical trials myelosuppression was generally reversible and usually managed by delaying next cycle and/or reducing days of treatment with Synribo [see Dosage and Administration (2.3) and Adverse Reactions (6.1)].

Bleeding

Synribo causes severe thrombocytopenia which increases the risk of hemorrhage. In clinical trials with CP and AP CML patients, a high incidence of Grade 3 and 4 thrombocytopenia (85% and 88%, respectively) was observed. Fatalities from cerebral hemorrhage occurred in 2% of patients treated with Synribo in the safety population. Severe, non-fatal, gastrointestinal hemorrhages occurred in 2% of patients in the same population. Most bleeding events were associated with severe thrombocytopenia.

Monitor platelet counts as part of the CBC monitoring as recommended [see Warnings and Precautions (5.1)]. Avoid anticoagulants, aspirin, and non-steroidal anti-inflammatory drugs (NSAIDs) when the platelet count is less than 50,000/µL as they may increase the risk of bleeding.

Hyperglycemia

Synribo can induce glucose intolerance. Grade 3 or 4 hyperglycemia was reported in 11% of patients in the safety population. Hyperosmolar non-ketotic hyperglycemia occurred in 1 patient treated with Synribo in the safety population. Monitor blood glucose levels frequently, especially in patients with diabetes or risk factors for diabetes. Avoid Synribo in patients with poorly controlled diabetes mellitus until good glycemic control has been established.

Embryo-Fetal Toxicity

Synribo can cause fetal harm when administered to a pregnant woman. Omacetaxine mepesuccinate caused embryo-fetal death in animals. Females of reproductive potential should avoid becoming pregnant while being treated with Synribo. There are no adequate and well-controlled studies of Synribo in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].

Adverse Reactions

The following serious adverse reactions have been associated with Synribo in clinical trials and are discussed in greater detail in other sections of the label.

•

Myelosuppression [see Warnings and Precautions (5.1)]

•

Bleeding [see Warnings and Precautions (5.2)]

•

Hyperglycemia [see Warnings and Precautions (5.3)]

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 safety data for Synribo are from 3 clinical trials which enrolled a total of 163 adult patients with TKI resistant and/or intolerant chronic phase (N=108) and accelerated phase (N=55) CML. All patients were treated with initial induction therapy consisting of a dose of 1.25 mg/m2 administered subcutaneously twice daily for 14 consecutive days every 28 days (induction cycle). Responding patients were then treated with the same dose and a twice daily schedule for 7 consecutive days every 28 days (maintenance cycle).

Chronic Phase CML

The median duration of exposure for the 108 patients with chronic phase CML was 7.4 months (range 0 to 43 months). The median total cycles of exposure was 6 (range 1 to 41), and the median total dose delivered during the trials was 131 mg/m2 (range 1.2 to 678). Among the patients with chronic phase CML, 87% received 14 days of treatment during cycle 1. By cycles 2 and 3, the percentage of patients receiving 14 days of treatment decreased to 42% and 16% respectively. Of the 91 patients who received at least 2 cycles of treatment, 79 (87%) had at least 1 cycle delay during the trials. The median number of days of cycle delays was greatest for cycle 2 (17 days) and cycle 3 (25 days) when more patients were receiving induction cycles.

Adverse reactions were reported for 99% of the patients with chronic phase CML. A total of 18% of patients had adverse reactions leading to withdrawal. The most frequently occurring adverse reactions leading to discontinuation were pancytopenia, thrombocytopenia, and increased alanine aminotransferase (each 2%). A total of 87% of patients reported at least 1 Grade 3 or Grade 4 treatment emergent adverse reaction (Table 2).

Table 2: Adverse Reactions Occurring* in at Least 10% of Patients (Chronic Myeloid Leukemia - Chronic Phase)
* Occurred in the period between the first dose and 30 days after the last dose. † Includes infusion related reaction, injection site erythema, injection site hematoma, injection site hemorrhage, injection site hypersensitivity, injection site induration, injection site inflammation, injection site irritation, injection site mass, injection site edema, injection site pruritus, injection site rash, and injection site reaction. ‡ Infection includes bacterial, viral, fungal, and non-specified.
	Number (%) of Patients (N=108)
Adverse reactions	All reactions	Grade 3 or 4 reactions
Patients with at least 1 commonly occurring adverse reaction	107 (99)	94 (87)
Blood and Lymphatic System Disorders
Thrombocytopenia	82 (76)	73 (68)
Anemia	66 (61)	39 (36)
Neutropenia	57 (53)	51 (47)
Lymphopenia	18 (17)	17 (16)
Bone Marrow Failure	11 (10)	11 (10)
Febrile Neutropenia	11 (10)	11 (10)
Gastrointestinal Disorders
Diarrhea	44 (41)	1 (1)
Nausea	38 (35)	1 (1)
Constipation	15 (14)	0
Abdominal Pain/Upper Abdominal Pain	25 (23)	0
Vomiting	13 (12)	0
General Disorders and Administration Site Conditions
Fatigue	31 (29)	5 (5)
Pyrexia	27 (25)	1 (1)
Asthenia	25 (23)	1 (1)
Edema Peripheral	17 (16)	0
Infusion and injection site related reactions†	38 (35)	0
Infections and Infestations‡	52 (48)	12 (11)
Metabolism and Nutrition Disorders
Anorexia	11 (10)	1 (1)
Musculoskeletal and Connective Tissue Disorders
Arthralgia	20 (19)	1 (1)
Pain in Extremity	14 (13)	1 (1)
Back Pain	13 (12)	2 (2)
Myalgia	12 (11)	1 (1)
Nervous System Disorders
Headache	22 (20)	1 (1)
Psychiatric Disorders
Insomnia	13 (12)	1 (1)
Respiratory, Thoracic and Mediastinal Disorders
Cough	17 (16)	1 (1)
Epistaxis	18 (17)	1 (1)
Skin and Subcutaneous Tissue Disorders
Alopecia	16 (15)	0
Rash	12 (11)	0

Serious adverse reactions were reported for 51% of patients. Serious adverse reactions reported for at least 5% of patients were bone marrow failure and thrombocytopenia (each 10%), and febrile neutropenia (6%). Serious adverse reactions of infections were reported for 8% of patients.

Deaths occurred while on study in five (5%) patients with CP CML. Two patients died due to cerebral hemorrhage, one due to multi-organ failure, one due to progression of disease, and one from unknown causes.

Accelerated Phase CML

Median total cycles of exposure was 2 (range 1 to 29), and the median total dose delivered during the trials was 70 mg/m2. The median duration of exposure for the 55 patients with accelerated phase CML was 1.9 months (range 0 to 30 months). Of the patients with accelerated phase CML, 86% received 14 days of treatment during cycle 1. By cycles 2 and 3, the percentage of patients receiving 14 days of treatment decreased to 55% and 44% respectively. Of the 40 patients who received at least 2 cycles of treatment, 27 (68%) had at least 1 cycle delay during the trials. The median number of days of cycle delays was greatest for cycle 3 (31 days) and cycle 8 (36 days).

Adverse reactions regardless of investigator attribution were reported for 100% patients with accelerated phase CML. A total of 33% of patients had adverse reactions leading to withdrawal. The most frequently occurring adverse reactions leading to withdrawal were leukocytosis (6%), and thrombocytopenia (4%). A total of 84% of patients reported at least 1 Grade 3 or Grade 4 treatment emergent adverse reaction (Table 3).

Table 3: Adverse Reactions Occurring* in at Least 10% of Patients (Chronic Myeloid Leukemia - Accelerated Phase)
* Occurred in the period between the first dose and 30 days after the last dose. † Includes infusion related reaction, injection site erythema, injection site hematoma, injection site hemorrhage, injection site hypersensitivity, injection site induration, injection site inflammation, injection site irritation, injection site mass, injection site edema, injection site pruritus, injection site rash, and injection site reaction. ‡ Infection includes bacterial, viral, fungal, and non-specified.
	Number (%) of Patients (N=55)
Adverse reactions	All reactions	Grade 3 or 4 reactions
Patients with at least 1 commonly occurring adverse reaction	55 (100)	47 (86)
Blood and Lymphatic System Disorders
Anemia	28 (51)	21 (38)
Febrile Neutropenia	11 (20)	9 (16)
Neutropenia	11 (20)	10 (18)
Thrombocytopenia	32 (58)	27 (49)
Gastrointestinal Disorders
Diarrhea	19 (35)	4 (7)
Nausea	16 (29)	2 (4)
Vomiting	9 (16)	1 (2)
Abdominal Pain/Upper Abdominal Pain	9 (16)	0
General Disorders and Administration Site Conditions
Fatigue	17 (31)	5 (9)
Pyrexia	16 (29)	1 (2)
Asthenia	13 (24)	1 (2)
Chills	7 (13)	0
Infusion and injection site related reactions†	12 (22)	0
Infections and Infestations‡	31 (56)	11 (20)
Metabolism and Nutrition Disorders
Anorexia	7 (13)	1 (2)
Musculoskeletal and Connective Tissue Disorders
Pain in Extremity	6 (11)	1 (2)
Nervous System Disorders
Headache	7 (13)	0
Respiratory, Thoracic and Mediastinal Disorders
Cough	8 (15)	0
Dyspnea	6 (11)	1 (2)
Epistaxis	6 (11)	1 (2)

Serious adverse reactions were reported for 60% of patients. Serious adverse reactions reported for at least 5% of patients were febrile neutropenia (18%), thrombocytopenia (9%), anemia (7%), and diarrhea (6%). Serious adverse reactions of infections were reported for 11% of patients.

Death occurred while on study in 5 (9%) patients with AP CML. Two patients died due to cerebral hemorrhage and three due to progression of disease.

Laboratory Abnormalities in Chronic and Accelerated Phase CML

Grade 3/4 laboratory abnormalities reported in patients with chronic and accelerated phase CML are described in Table 4. Myelosuppression occurred in all patients treated with Synribo [see Warnings and Precautions (5.1)]. Five patients with chronic phase CML and 4 patients with accelerated phase CML permanently discontinued Synribo due to pancytopenia, thrombocytopenia, febrile neutropenia, or bone marrow necrosis. An event of hyperosmolar non-ketotic hyperglycemia was reported in one patient in the safety population and a similar case has been reported in the literature. Two patients with chronic phase CML permanently discontinued Synribo due to elevated transaminases.

Table 4: Grade 3/4 Laboratory Abnormalities in Clinical Studies in Patients with Chronic Phase and Accelerated Phase CML
	Chronic Phase	Accelerated Phase
	%	%
Hematology Parameters
Hemoglobin Decreased	62 72	80
Leukocytes Decreased		61
Neutrophils Decreased	81 85	71
Platelets Decreased		88
Biochemistry Parameters
Alanine aminotransferase (ALT) Increased	6	2
Bilirubin Increased Creatinine Increased	9 9	6 16
Glucose Increased	10	15
Uric Acid Increased	56	57
Glucose Decreased	8	6

Additional Data from Safety Population

The following adverse reactions were reported in patients in the Synribo clinical studies of patients with chronic phase and accelerated phase CML at a frequency of 1% to less than 10%. Within each category, adverse reactions are ranked on the basis of frequency.

Cardiac Disorders: tachycardia, palpitations, acute coronary syndrome, angina pectoris, arrhythmia, bradycardia, ventricular extrasystoles.

Ear and Labyrinth Disorders: ear pain, ear hemorrhage, tinnitus.

Eye Disorders: cataract, vision blurred, conjunctival hemorrhage, dry eye, lacrimation increased, conjunctivitis, diplopia, eye pain, eyelid edema.

Gastrointestinal Disorders: stomatitis, mouth ulceration, abdominal distension, dyspepsia, gastroesophageal reflux disease, gingival bleeding, aphthous stomatitis, dry mouth, hemorrhoids, gastritis, gastrointestinal hemorrhage, melena, mouth hemorrhage, oral pain, anal fissure, dysphagia, gingival pain, gingivitis.

General Disorders and Administration Site Conditions: mucosal inflammation, pain, chest pain, hyperthermia, influenza-like illness, catheter site pain, general edema, malaise.

Immune System Disorders: hypersensitivity.

Injury, Poisoning and Procedural Complications: contusion, transfusion reaction.

Metabolism and Nutrition Disorders: decreased appetite, diabetes mellitus, gout, dehydration.

Musculoskeletal and Connective Tissue Disorders: bone pain, myalgia, muscular weakness, muscle spasms, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal stiffness, musculoskeletal discomfort.

Nervous System Disorders: dizziness, cerebral hemorrhage, paresthesia, convulsion, hypoesthesia, lethargy, sciatica, burning sensation, dysgeusia, tremor.

Psychiatric Disorders: anxiety, depression, agitation, confusional state, mental status change.

Renal and Urinary Disorders: dysuria.

Respiratory, Thoracic and Mediastinal Disorders: pharyngolaryngeal pain, nasal congestion, dysphonia, productive cough, rales, rhinorrhea, hemoptysis, sinus congestion.

Skin and Subcutaneous Tissue Disorders: erythema, pruritus, dry skin, petechiae, hyperhidrosis, night sweats, ecchymosis, purpura, skin lesion, skin ulcer, rash erythematous, rash papular, skin exfoliation, skin hyperpigmentation.

Vascular Disorders: hematoma, hypertension, hot flush, hypotension.

USE IN SPECIFIC POPULATIONSPregnancy

Pregnancy Category D [see Warnings and Precautions (5.4)]

Risk Summary

Based on its mechanism of action and findings from animal studies, Synribo can cause fetal harm when administered to pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Animal Data

In an embryo-fetal development study, pregnant mice were administered omacetaxine mepesuccinate subcutaneously during the period of organogenesis at doses of 0.21 or 0.41 mg/kg/day. Drug-related adverse effects included embryonic death, an increase in unossified bones/reduced bone ossification and decreased fetal body weights. Fetal toxicity occurred at doses of 0.41 mg/kg (1.23 mg/m2) which is approximately half the recommended daily human dose on a body surface area basis.

Nursing Mothers

It is not known whether omacetaxine mepesuccinate is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reaction in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

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

Geriatric Use

In the chronic and accelerated phase CML efficacy populations 23 (30%) and 16 (46%) patients were ≥65 years of age. For the age subgroups of <65 years of age and ≥65 years of age, there were differences between the subgroups, with higher rates of major cytogenetic responses (MCyRs) in younger patients with CP CML compared with older patients (23% vs. 9%, respectively) and higher rates of major hematologic responses (MaHRs) in older patients with AP CML compared with younger patients (31% vs. 0%, respectively). Patients ≥65 years of age were more likely to experience toxicity, most notably hematologic toxicity.

Effect of Gender

Of the 76 patients included in the chronic phase CML population efficacy analysis, 47 (62%) of the patients were men and 29 (38%) were women. For patients with chronic phase CML, the MCyR rate in men was higher than in women (21% vs. 14%, respectively). There were differences noted in the safety profile of omacetaxine mepesuccinate in men and women with chronic phase CML although the small number of patients in each group prevents a definitive assessment. There were inadequate patient numbers in the accelerated phase subset to draw conclusions regarding a gender effect on efficacy.

Overdosage

A patient in the clinical expanded access program received an overdose of 2.5 mg/m2 twice daily for 5 days in the 16th cycle. The patient presented with gastrointestinal disorders, gingival hemorrhage, alopecia, and Grade 4 thrombocytopenia and neutropenia. When Synribo treatment was temporarily interrupted the gastrointestinal disorders and hemorrhagic syndrome resolved, and neutrophil values returned to within normal range. The alopecia and thrombocytopenia (Grade 1) improved, and Synribo was restarted.

No specific antidote for Synribo overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters.

Synribo Description

Synribo contains the active ingredient omacetaxine mepesuccinate, a cephalotaxine ester. It is a protein synthesis inhibitor. Omacetaxine mepesuccinate is prepared by a semi-synthetic process from cephalotaxine, an extract from the leaves of Cephalotaxus sp. The chemical name of omacetaxine mepesuccinate is cephalotaxine, 4-methyl (2R)-hydroxyl-2-(4-hydroxyl-4-methylpentyl) butanedioate (ester).

Omacetaxine mepesuccinate has the following chemical structure:

The molecular formula is C29H39NO9 with a molecular weight of 545.6 g/mol. Synribo for Injection is a sterile, preservative-free, white to off-white, lyophilized powder in a single-dose vial. Each vial contains 3.5 mg omacetaxine mepesuccinate and mannitol.

Synribo is intended for subcutaneous administration after reconstitution with 1.0 mL of 0.9% Sodium Chloride Injection, USP. The pH of the reconstituted solution is between 5.5 and 7.0.

Synribo - Clinical PharmacologyMechanism of Action

The mechanism of action of omacetaxine mepesuccinate has not been fully elucidated but includes inhibition of protein synthesis and is independent of direct Bcr-Abl binding. Omacetaxine mepesuccinate binds to the A-site cleft in the peptidyl-transferase center of the large ribosomal subunit from a strain of archaeabacteria. In vitro, omacetaxine mepesuccinate reduced protein levels of the Bcr-Abl oncoprotein and Mcl-1, an anti-apoptotic Bcl-2 family member. Omacetaxine mepesuccinate showed activity in mouse models of wild-type and T315I mutated Bcr-Abl CML.

Pharmacodynamics

Cardiac Electrophysiology

In an uncontrolled pharmacokinetic study there were no reports of QTcF > 480 ms or ΔQTcF > 60 ms in 21 treated patients who received omacetaxine mepesuccinate 1.25 mg/m2 BID for 14 consecutive days. There was no evidence for concentration-dependent increases in QTc for omacetaxine mepesuccinate or 4’-DMHHT. Although the mean effect on QTc was 4.2 ms (upper 95% CI: 9.5 ms), QTc effects less than 10 ms cannot be verified due to the absence of a placebo and positive controls.

Pharmacokinetics

The dose proportionality of omacetaxine mepesuccinate is unknown. A 90% increase in systemic exposure to omacetaxine mepesuccinate was observed between the first dose and steady state.

Absorption

The absolute bioavailability of omacetaxine mepesuccinate has not been determined. Omacetaxine mepesuccinate is absorbed following subcutaneous administration, and maximum concentrations are achieved after approximately 30 minutes.

Distribution

The steady-state (mean ± SD) volume of distribution of omacetaxine mepesuccinate is approximately 141 ± 93.4 L following subcutaneous administration of 1.25 mg/m2 twice daily for 11 days . The plasma protein binding of omacetaxine mepesuccinate is less than or equal to 50%.

Elimination

The terminal elimination half-life of omacetaxine mepesuccinate in plasma is 14.6 hours.

Metabolism

Omacetaxine mepesuccinate is primarily hydrolyzed to 4′-DMHHT via plasma esterases with little hepatic microsomal oxidative and/or esterase-mediated metabolism in vitro.

Excretion

Following a single subcutaneous dose of radiolabeled omacetaxine mepesuccinate, the mean total recovery of radioactivity in excreta was approximately 81% of the radioactive dose. Approximately 37% of the radioactivity was recovered in urine and approximately 44% in feces.

Drug Interaction Studies

Cytochrome P450 (CYP) Enzymes: Omacetaxine mepesuccinate and 4′-DMHHT do not inhibit major CYP enzymes in vitro at concentrations that can be expected clinically. The potential for omacetaxine mepesuccinate or 4′-DMHHT to induce CYP enzymes has not been determined.

Transporter Systems: Omacetaxine mepesuccinate is a P-glycoprotein (P-gp) substrate in vitro. Omacetaxine mepesuccinate and 4′-DMHHT do not inhibit P-gp mediated efflux of loperamide in vitro at concentrations that can be expected clinically.

Nonclinical ToxicologyCarcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity studies have been conducted with omacetaxine mepesuccinate.

Omacetaxine mepesuccinate was genotoxic in an in vitro chromosomal aberration test system in Chinese hamster ovary (CHO) cells, but was not mutagenic when tested in an in vitro bacterial cell assay (Ames test), and it did not induce genetic damage using an in vivo mouse micronucleus assay.

Synribo may impair male fertility. Studies in mice demonstrated adverse effects on male reproductive organs. Bilateral degeneration of the seminiferous tubular epithelium in testes and hypospermia/aspermia in the epididymides were reported in the highest dose group (2.33 mg/kg/day reduced to 1.67 mg/kg/day; 7 to 5 mg/m2/day) following subcutaneous injection of omacetaxine mepesuccinate for six cycles over six months. The doses used in the mice were approximately two to three times the clinical dose (2.5 mg/m2/day) based on body surface area.

Clinical Studies

The efficacy of Synribo was evaluated using a combined cohort of adult patients with CML from two trials. The combined cohort consisted of patients who had received 2 or more approved TKIs and had, at a minimum, documented evidence of resistance or intolerance to dasatinib and/or nilotinib. Resistance was defined as one of the following: no complete hematologic response (CHR) by 12 weeks (whether lost or never achieved); or no cytogenetic response by 24 weeks (i.e., 100% Ph positive [Ph+]) (whether lost or never achieved); or no major cytogenetic response (MCyR) by 52 weeks (i.e., ≥35% Ph+) (whether lost or never achieved); or progressive leukocytosis. Intolerance was defined as one of the following: 1) Grade 3-4 non-hematologic toxicity that does not resolve with adequate intervention; or 2) Grade 4 hematologic toxicity lasting more than 7 days; or 3) any Grade ≥ 2 toxicity that is unacceptable to the patient. Patients with NYHA class III or IV heart disease, active ischemia or other uncontrolled cardiac conditions were excluded.

Patients were treated with omacetaxine mepesuccinate at a dose of 1.25 mg/m2 administered subcutaneously twice daily for 14 consecutive days every 28 days (induction cycle). Responding patients were then treated with the same dose and twice daily schedule for 7 consecutive days every 28 days (maintenance cycle). Patients were allowed to continue to receive maintenance treatment for up to 24 months. Responses were adjudicated by an independent Data Monitoring Committee (DMC).

Chronic Phase CML (CP CML)

A total of 76 patients with chronic phase CML were included in the efficacy analysis. The demographics were: median age 59 years, 62% were male, 30% were 65 years of age or older, 80% were Caucasian, 5% were African-American, 4% were Asian and 4% were Hispanic. Thirty-six (47%) patients had failed treatment with imatinib, dasatinib, and nilotinib. Most patients had also received prior non-TKI treatments, most commonly hydroxyurea (54%), interferon (30%), and/or cytarabine (29%). The efficacy endpoint was based on MCyR (adjudicated by a DMC).

 

Table 5: Efficacy Results Evaluated by DMC for Patients with CP CML

	Patients (N=76)
Primary Response – MCyR
Total with MCyR, n (%)	14 (18.4)
95% confidence interval	(10.5% – 29.0%)
Cytogenetic Response, n (%)
Confirmed complete	6 (7.9)
Confirmed partial	3 (3.9)

 

Cytogenetic response evaluation is based on standard cytogenetic analysis (at least 20 metaphases).
Complete: 0% Ph+ cells, Partial > 0% to 35% Ph+ cells

The mean time to MCyR onset in the 14 patients was 3.5 months. The median duration of MCyR for the 14 patients was 12.5 months (Kaplan-Meier estimate).

Accelerated Phase CML (AP CML)

A total of 35 patients with accelerated phase CML were included in the efficacy analysis. The demographics were: median age was 63 years, 57% were male, 46% were 65 years of age or older, 68% were Caucasian, 23% were African-American, 3% were Asian and 3% were Hispanic. Twenty-two (63%) of 35 patients with accelerated phase had failed treatment with imatinib, dasatinib, and nilotinib. Most patients had also received prior non-TKI treatments, most commonly hydroxyurea (43%), interferon (31%), and/or cytarabine (29%). The efficacy endpoint was assessed based on MCyR and MaHR (complete hematologic response [CHR] or no evidence of leukemia [NEL]). The efficacy results for the patients with accelerated phase as adjudicated by the DMC are shown in Table 6.

 

Table 6: Efficacy Results Evaluated by DMC for Patients with AP CML

	Patients (N=35)
Primary Response – MaHR
Total with MaHR, n (%)	5 (14.3)
95% confidence interval	(4.5% - 30.3%)
CHR	4 (11.4)
NEL	1 (2.9)
Primary Response – MCyR
Total with MCyR, n (%)	0

 

MaHR is defined as complete hematologic response (CHR) or no evidence of leukemia (NEL): CHR - absolute neutrophil count ≥ 1.5 × 109/liter, platelets ≥ 100 × 109/liter, no blood blasts, bone marrow blasts < 5%, no extramedullary disease; NEL - Morphologic leukemia-free state, defined as <5% bone marrow blasts.

The mean time to response onset in the 5 patients was 2.3 months. The median duration of MaHR for the 5 patients was 4.7 months (Kaplan-Meier estimate).

REFERENCES

1.

OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

How Supplied/Storage and HandlingHow Supplied

Synribo (omacetaxine mepesuccinate) for Injection is supplied in 8 mL clear glass single-dose vial in individual cartons. Each vial contains 3.5 mg of Synribo (omacetaxine mepesuccinate) for Injection (NDC 63459-177-14).

Storage and Handling

Store unopened vials at 20oC to 25ºC (68o F to 77ºF); excursions permitted from 15ºC to 30ºC (59ºF to 86ºF) [see USP Controlled Room Temperature]. Prior to re-constitution, keep product in carton to protect from light.

Omacetaxine mepesuccinate is a cytotoxic drug. Follow special handling and disposal procedures1.

Patient Counseling Information

Availability of Medication Guide and Instructions for Use

Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Assist patients and caregivers in understanding their contents and give them the opportunity to discuss the contents of the Medication Guide and Instructions for Use and to obtain answers to any questions they may have prior to initiating therapy. The complete text of the Medication Guide and Instructions for Use are attached to the prescribing information.

Patient Training

Once it is determined that a patient is an appropriate candidate for self-administration or administration by a caregiver, ensure that patients receive the necessary supplies for home administration of Synribo and train them on the following [see Dosage and Administration (2.4, 2.5, 2.6, 2.7)]:

•

How to transport reconstituted Synribo in a secure container or packaging and under recommended temperature conditions

•

Acceptable storage conditions and use times for reconstituted Synribo

∘

When stored in a refrigerator (2°C to 8°C [36°F to 46°F]), use within 6 days (144 hours)

∘

When stored at room temperature (not to exceed 25°C [77°F]), use within 12 hours

•

If stored in a refrigerator, keep Synribo from coming into contact with food or drink.

•

To wear disposable gloves and protective eyewear when handling Synribo.

•

To wash hands before putting on gloves and after removing gloves.

•

Not to eat or drink while handling Synribo. To administer Synribo in an area away from food or food preparation areas.

•

To administer Synribo in a location away from children and pregnant women.

•

Proper subcutaneous injection technique including acceptable sites.

•

The importance of body site selection for administering the injection, as well as the importance of alternating the injection sites. Advise patients to not inject Synribo into areas of the skin that are tender, red, bruised, hard, or that have scars or stretch marks.

•

In the case of a missed dose: If a patient misses an injection, skip the missed dose and the patient should give the next scheduled injection at the next scheduled time. Inform patients NOT to give two injections to make up for a missed injection.

•

In the case that Synribo comes into contact with a patient’s skin or eyes: Advise patients to wash exposed skin with soap and water and in the case of eye exposure, thoroughly flush the eye with water. After washing or flushing, advise patients to call their healthcare provider immediately.

•

In the case that too much Synribo is injected or that Synribo is accidentally swallowed: Instruct patients to contact their healthcare provider immediately if they have injected too much Synribo, or if someone has swallowed Synribo.

•

Disposal procedures, including use of an appropriate biohazard container and return of the container to the clinic or pharmacy for final disposal. Inform patients NOT to recap or clip the used needle and not to place used needles, syringes, vials, and other used supplies in a household trash or recycle container.

•

Accidental spillage procedures, including wiping the spilled liquid with the absorbent pad (using protective eyewear and gloves), washing the area with water and soap, and proper disposal of materials.

Myelosuppression

Advise patients of the likelihood that Synribo will cause a decrease in white blood cells, platelets, and red blood cells and that monitoring of these parameters will be needed. Instruct patients to contact a health care professional if they develop a fever, or other signs/symptoms of infection; shortness of breath, significant fatigue, or bleeding [see Warnings and Precautions (5.1)].

Bleeding

Advise patients of the possibility of serious bleeding due to low platelet counts. Instruct patients to report immediately any signs or symptoms suggestive of hemorrhage (unusual bleeding, easy bruising or blood in urine or stool; confusion, slurred speech, or altered vision). Instruct patients to report in advance if they plan to have any dental or surgical procedures [see Warnings and Precautions (5.2)].

Hyperglycemia

Advise patients with diabetes of the possibility of hyperglycemia and the need for careful monitoring of blood glucose levels. Patients with poorly controlled diabetes mellitus should not be treated with omacetaxine mepesuccinate until good glycemic control has been established [see Warnings and Precautions (5.3)].

Pregnancy and Nursing

Advise patients that omacetaxine mepesuccinate can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential of the potential hazard to the fetus and to avoid becoming pregnant [see Warnings and Precautions (5.4)]. Advise females to avoid nursing while receiving Synribo [see Use in Specific Populations (8.3)].

Gastrointestinal Distress

Advise patients that they may experience nausea, diarrhea, abdominal pain, constipation, and vomiting. If these symptoms persist, they should seek medical attention.

Fatigue

Advise patients that Synribo may cause tiredness and to avoid driving any vehicle or operating any dangerous tools or machinery if they experience this side effect.

Rash

Advise patients that they may experience skin rash. Advise patients to immediately report severe or worsening rash or itching.

Alopecia

Advise patients that they may experience hair loss.

SYN-005

Distributed by:

Teva Pharmaceuticals USA, Inc.

North Wales, PA 19454

MEDICATION GUIDE

Synribo® (sin-RYE-bo)
(omacetaxine mepesuccinate)
for injection, for subcutaneous use

Read this Medication Guide before you start using Synribo and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.

What is the most important information I should know about Synribo?

Synribo can cause serious side effects including:

Low blood counts. Low blood counts are common when using Synribo, including low red blood cells, white blood cells, and platelets, and can be severe. If your white blood cell count becomes very low, you are at increased risk for infection which can lead to death. Your healthcare provider will check your blood counts regularly during treatment with Synribo. Tell your healthcare provider right away if you get any of the following symptoms:

• fever	• feeling very tired
• chills	• shortness of breath
• body aches	• bleeding (see below)

Bleeding. Synribo causes severe low platelet counts that may increase your risk of severe bleeding. Severe low platelet counts can cause you to have bleeding in your brain or severe stomach bleeding, that can lead to death. Your healthcare provider will check your platelet counts regularly during treatment with Synribo. Tell your healthcare provider right away if you get any of the following symptoms:

• unusual bleeding	• confusion
• easy bruising	• slurred speech
• blood in urine or stool	• vision changes

See “What are the possible side effects of Synribo?” for more information about side effects.

What is Synribo?

Synribo is a prescription medicine used to treat adults with a type of blood cancer (leukemia) called chronic myeloid leukemia (CML):

•

that is in the chronic phase or accelerated phase, and

•

who have not responded to (resistant) or cannot tolerate 2 or more medicines called tyrosine kinase inhibitors.

It is not known if Synribo is safe and effective in children.

What should I tell my healthcare provider before using Synribo?

Before using Synribo, tell your healthcare provider if you:

•

have diabetes or a family history of diabetes

•

have bleeding problems

•

plan to have any dental or surgical procedures

•

have any other medical problems

•

are pregnant or plan to become pregnant. Synribo can harm your unborn baby. You should not become pregnant during treatment with Synribo. Tell your healthcare provider right away if you become pregnant during treatment with Synribo.

•

are breastfeeding or plan to breastfeed. It is not known if Synribo passes into your breast milk. You and your healthcare provider should decide if you will take Synribo or breastfeed. You should not do both.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

How should I use Synribo?

•

Follow the detailed Instructions for Use at the end of this Medication Guide for information about the right way to:

∘

properly handle and inject Synribo

∘

dispose of used supplies for injecting Synribo

∘

clean up any spilled Synribo

•

Your healthcare provider will tell you how much Synribo to inject and the timing of when to inject it. Inject Synribo exactly as prescribed.

•

Do not change your dose or the timing of when you inject Synribo, unless your healthcare provider tells you to.

•

Synribo is given as an injection under the skin (subcutaneous injection) of your thigh or stomach-area (abdomen). The injection can be given in the back of the arm if a caregiver is giving the injection.

•

If your healthcare provider decides that you or a caregiver can inject Synribo, your healthcare provider will show you or your caregiver how to prepare for an injection and how to inject Synribo before you use it for the first time.

•

Synribo is injected 2 times each day, about every 12 hours.

•

Your healthcare provider may tell you to stop using Synribo for a period of time, or tell you to use Synribo less often depending on the side effects that you get.

•

Your healthcare provider will arrange for you to receive syringes filled with Synribo that are ready to inject, along with the other supplies that you will need to inject Synribo. Each syringe contains 1 dose of Synribo as prescribed by your healthcare provider.

•

Follow your healthcare provider’s instructions for how to carry (transport) Synribo using ice packs or a cooler.

•

Do not eat or drink while handling Synribo.

•

You or your caregiver should wear gloves and protective eyewear, for example protective eyeglasses (not regular eyeglasses) or face shield when handling Synribo and while giving your injection.

•

If you or your caregiver get Synribo on your skin, wash the area with soap and water.

•

If you or your caregiver get Synribo in your eyes, flush your eyes with water and call your healthcare provider right away.

•

If you miss a dose of Synribo, just skip the missed dose. Give your next injection of Synribo at your next scheduled time. Do not give 2 doses of Synribo at the same time to make up for a missed dose.

•

If you inject too much Synribo, call your healthcare provider or go to the nearest emergency room right away. Follow your healthcare provider’s instructions for when you should inject your next dose of Synribo.

•

If another person accidentally injects themself with Synribo, or if anyone accidentally swallows Synribo, call your doctor or get emergency help right away.

What should I avoid while using Synribo?

Synribo may cause tiredness. Avoid driving, or operating dangerous tools or machinery if you develop tiredness when using Synribo.

What are the possible side effects of Synribo?

Synribo may cause serious side effects, including:

•

See “What is the most important information I should know about Synribo?”

•

High blood sugar levels (hyperglycemia). Synribo can cause high blood sugar levels. If you have diabetes or are at risk for diabetes, your healthcare provider will check your blood glucose levels often during treatment with Synribo. If you have diabetes or if your blood sugar is not well controlled, your healthcare provider may decide not to start treatment with Synribo until your diabetes is under control first.

The most common side effects of Synribo are:

•

Infections. See the information about low blood cell counts in the section “What is the most important information I should know about Synribo?”

•

diarrhea

•

nausea

•

tiredness

•

weakness

•

redness, swelling, or pain at injection site

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all of the side effects of Synribo. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Synribo?

•

Carry (transport) Synribo as instructed by your healthcare provider. It is important to use ice packs or a cooler.

•

When stored in a refrigerator 36°F to 46°F (2°C to 8°C), use Synribo within 6 days from when it was mixed.

•

When stored at room temperature, 68°F to 77°F (20°C to 25°C), use Synribo within 12 hours from when it was mixed.

•

When stored in a refrigerator, keep Synribo from coming into contact with food or drink

Keep Synribo and all medicines out of the reach of children.

General information about the safe and effective use of Synribo.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Synribo for a condition for which it was not prescribed. Do not give Synribo to other people even if they have the same symptoms you have. It may harm them.

If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Synribo that is written for health professionals.

For more information, go to www.Synribo.com or call Teva at 1-800-896-5855.

What are the ingredients in Synribo?

Active ingredient: omacetaxine mepesuccinate

Inactive ingredients: mannitol

This Medication Guide has been approved by the U.S. Food and Drug Administration.

 

Distributed by:

Teva Pharmaceuticals USA, Inc.

North Wales, PA 19454

SYNMG-001

Issued: April 2014

Instructions for Use

Synribo® (sin-RYE-bo)
(omacetaxine mepesuccinate)
for injection, for subcutaneous use

Read this Instructions for Use before you inject Synribo for the first time and each time you get a refill. Also read the Medication Guide for Synribo.

Before you or your caregiver injects Synribo, your healthcare provider will show you how to properly:

•

handle syringes and inject Synribo

•

dispose of used supplies for injecting Synribo

•

clean up any spilled Synribo

Important:

•

Be sure that you store Synribo exactly as your healthcare provider tells you to. See the section “How should I store Synribo?” in the Medication Guide.

•

Never try to re-cap the needle. This could cause a needle-stick injury.

•

If Synribo comes into contact with your skin, wash the area well with soap and water.

Your healthcare provider will arrange for you to receive all of the supplies that you will need for each injection of Synribo:

•

syringe with attached needle, containing Synribo for injection

•

protective eyewear, such as protective eyeglasses (not regular eyeglasses) or face shield

•

gloves

•

disposal biohazard container

•

absorbent pads for use to clean up an accidental spill of Synribo

•

alcohol swabs

•

gauze pads

You may also need an adhesive bandage.

Never mix Synribo yourself. If you don’t receive syringes already filled with Synribo, contact your doctor or pharmacy.

Step 1. Preparing to give an injection of Synribo.

•

Find a clean flat work surface.

•

Wash your hands well with soap and water.

•

Put on a pair of gloves and your protective eyewear before you handle the syringe containing Synribo. Wearing gloves and protective eyewear protects you from splashes or spills. See Figure A.

•

Look at the date printed on the syringe label to make sure that the expiration date has not passed. Do not use if the expiration date has passed and contact your doctor or pharmacy immediately.

•

Gather the rest of your supplies and place them on your work surface.

Figure A

Step 2. Choose an injection site.

•

You may inject Synribo into your thigh or stomach-area (abdomen). See Figure B. The injection can be given in the back of your arm if a caregiver is giving the injection. See Figure C.

•

Use a different site for each injection to help decrease tenderness at the injection site. Each injection site should be at least 1 inch away from any recently used injection site.

•

Do not inject Synribo into areas of your skin that are tender, red, bruised, hard, or that have scars or stretch marks.

 

Figure B Figure C

Step 3. Prepare the injection site.

•

Clean the injection site well with an alcohol wipe and allow it to air dry. See Figure D.

Figure D

Step 4. Inject Synribo.

•

Carefully remove the needle cap by pulling, taking care not to stick yourself. See Figure E.

•

Do not press down on the plunger.

Figure E

•

With one hand, pinch skin of injection site between your thumb and forefinger. See Figure F.

Figure F

•

With your other hand, hold the syringe at a 45 degree or 90 degree angle to your skin. Use a quick dart-like motion to insert the needle through the skin at the injection site. See Figures G and H. The needle should go through the skin but not into your muscle.

 

Figure G Figure H

•

Slowly push down on the plunger with your thumb until syringe is empty. See Figure I.

Figure I

•

Stop pinching your skin. Quickly remove needle and then apply pressure on injection site with a dry gauze pad. You can put a small adhesive bandage over the injection site if there is bleeding. See Figure J.

Figure J

•

Follow the instructions below for how to dispose of the syringe, needle, and other supplies used to give your injection. Never try to re-cap the needle. This could cause a needle-stick injury.

•

Remove your gloves. Wash your hands right away with soap and water, and then remove your protective eyewear.

How should I throw away (dispose of) used Synribo syringes, needles, and other supplies?

•

Throw away (dispose of) used Synribo syringes, needles, and other used supplies in an appropriate biohazard container.

•

Return the biohazard container to your healthcare provider for disposal.

•

Do not place used syringes, needles, or other supplies in a household trash or recycle container. Do not re-cap or clip the used needle. This could cause a needle-stick injury.

•

Do not throw away the protective eyewear. You will need them for each dose of Synribo.

What should I do in case of an accidental Synribo spill?

•

Your healthcare provider will arrange for you to receive supplies to use in case you spill Synribo.

•

Follow your healthcare provider’s instructions about how to clean up a Synribo spill.

•

Do not touch a spill unless you are wearing gloves and protective eyewear.

•

Use an absorbent pad to wipe up the spill. Wash the area with soap and water. Use an extra absorbent pad or paper towel to dry the area.

•

Place the pad, gloves, and other supplies that were used to clean the spill in the biohazard container.

•

Call your healthcare provider right away to report the spill.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

 

Distributed by:

Teva Pharmaceuticals USA, Inc.

North Wales, PA 19454

SYNIFU-002

Issued: December 2015

Package/Label Display Panel, Part 1 of 3

Package/Label Display Panel, Part 2 of 3

Package/Label Display Panel, Part 3 of 3

Synribo® (omacetaxine mepesuccinate) for Injection 3.5 mg/vial, Single-Use Vial Carton Text

 

NDC 63459-177-14 Rx only

Single-Use Vial.

Discard unused portion.

Synribo®

(omacetaxine mepesuccinate)

for Injection

3.5 mg/vial

For Subcutaneous Use Only

Must be Reconstituted Before Use

Medication Guide Required: Each time

Synribo is dispensed, give the patient a

Medication Guide.

Distributed by:

Teva Pharmaceuticals USA, Inc.

North Wales, PA 19454

TEVA

Synribo omacetaxine mepesuccinate injection, powder, lyophilized, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:63459-177 Route of Administration SUBCUTANEOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength OMACETAXINE MEPESUCCINATE (OMACETAXINE) OMACETAXINE MEPESUCCINATE 3.5 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength MANNITOL

Packaging # Item Code Package Description   1 NDC:63459-177-14 1 VIAL, SINGLE-USE in 1 CARTON   1   1 mL in 1 VIAL, SINGLE-USE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA203585 11/19/2012

Labeler - Cephalon, Inc. (183236314)

 

Cephalon, Inc.