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XOSPATA® (gilteritinib)片使用说明书
这些重点不包括安全和有效使用XOSPATA 需所有资料。请参阅XOSPATA 完整处方资料
XOSPATA® (gilteritinib)片，为口服使用
美国初始批准: 2018
适应证和用途
XOSPATA是一种激酶抑制剂适用为的治疗成年患者有复发的或难治的急性髓性白血病(AML)有一个FLT3突变如被FDA-批准的测试检测 (1.1)
剂量和给药方法
120 mg口服每天1次。 (2.2)
剂型和规格
片: 40 mg. (3)
禁忌证
对gilteritinib超敏性或赋形剂的任何。在临床试验中曽被观察到。(4，6.1)
警告和注意事项
• 后部可逆性脑病综合征(PRES): 在患者发生 PRES终止XOSPATA. (2.3，5.1，6.1)
• 延长的QT间期: 中断和减低XOSPATA剂量在患者有一个QTcF >500 msec。纠正低钾血症或低镁血症 XOSPATA给药前和期间 (2.3，5.2，12.2，6.1)
• 胰腺炎:在发生胰腺炎患者中中断和减低剂量。 (2.3，5.3)
• 胚胎胎儿毒性: XOSPATA可致胎儿致命性危害当给予至一位妊娠女。忠告对一个胎儿潜在风险和使用有效避孕。(5.4，8.1，8.3)
不良反应
最常见不良反应(≥20%)为肌痛/关节痛，转氨酶增加，疲乏/无力，发热，非感染性腹泻，呼吸困难，水肿，皮疹，肺炎，恶心，口炎，咳嗽，头痛，低血压，眩晕和呕吐。(6.1)
报告怀疑不良反应，联系Astellas Pharma US，Inc.电话1-800-727-7003或FDA电话1-800-FDA-1088或www.fda.gov/medwatch。
药物相互作用
• 组合P-gp和强 CYP3A诱导剂: 避免同时使用。(7.1)
• 强 CYP3A抑制剂: 考虑另外治疗。如同时使用强 CYP3A抑制剂不能避免，监视患者更频对XOSPATA不良反应。 (2.3，7.1)
在特殊人群中使用
哺乳: 忠告患者不要哺乳喂养。(8.2)
完整处方资料
1 适应证和用途
1.1 复发的或难治的急性髓性白血病
XOSPATA是适用为的治疗成年患者有复发的或难治的急性髓性白血病(AML)有一个FMS-样酪氨酸激酶3 (FLT3)突变如被FDA-批准的测试检测
2 剂量和给药方法
2.1 患者选择
根据FLT3 突变在血中或骨髓中的存在选择患者用 XOSPATA对AML的治疗 [见临床研究(14)]。对FDA-批准的测试为一个FLT3突变在AML中的检测的资料是在以下网址中可得到http://www.fda.gov/CompanionDiagnostics。
2.2 推荐剂量
XOSPATA的推荐开始剂量120 mg口服每天1次有或无食物。反应可能被延迟。在缺乏疾病进展或不能接受毒性，被推荐治疗共最小6个月允许时间对一个临床反应。不要破坏或压碎XOSPATA片。给予 XOSPATA片口服每天大约相同时间。如一剂XOSPATA被缺失或没有在寻常时间服用，尽可能马上给予和在相同天，和至少下一次计划时间前12小时。返回至以后天正常时间表。不要在12小时内给予2剂。 
2.3 剂量修饰
XOSPATA的开始前评估血细胞计数和血液化学，包括肌酐磷酸激酶，至少每周1次对第一个月，对第二个月每隔天1次，和对治疗期间每月1次。疗程1用gilteritinib开始治疗前，在天8和15，和下两个随后疗程开始前进行心电图(ECG)。中断给药或减低剂量对毒性如每表1。
 






3 剂型和规格
40 mg 片: 浅黄色，圆形膜-包衣片凹陷有Astellas标志和‘235’在相同侧。
4 禁忌证
XOSPATA被禁忌在患者有对gilteritinib或赋形剂的任何有超敏性。在临床试验中曽观察到过敏反应[见不良反应(6)和描述(11)]。
5 警告和注意事项
5.1 后部可逆性脑病综合征
曽有罕见报道的后部可逆性脑病综合征(PRES)有症状包括癫痫和用XOSPATA改变的精神状态。XOSPATA的终止后症状曽解决。PRES的一个诊断需要确证通过脑影像，更合适地核磁共振影像 (MRI)。终止XOSPATA在患者发生PRES[见剂量和给药方法(2.3)和不良反应(6.1)]。
5.2 延长的QT间期
XOSPATA曽被伴随延长心室复极化(QT间期)。在临床试验中292用XOSPATA治疗患者，1.4% 被发现有一个 QTc间期大于500 msec和7%的患者有一个从基线增加QTc大于60 msec。疗程1的天8和15和下一个两个随后疗程的开始前用gilteritinib治疗的开始前进行心电图(ECG)。中断和减低XOSPATA剂量在患者有一个QTcF >500 msec[见剂量和给药方法(2.3)，不良反应(6.1)和临床药理学(12.2)]。低钾血症或低镁血症可能增加QT延长风险。XOSPATA给药前和期间纠正低钾血症或低镁血症。
5.3 胰腺炎
在临床试验中在接受XOSPATA患者中曽有胰腺炎的罕见报道。评价发生胰腺炎的体征和症状患者。在发生胰腺炎患者中中断和减低XOSPATA的剂量[见剂量和给药方法(2.3)]。
5.4 胚胎胎儿毒性
根据动物中发现和它的作用机制，XOSPATA可能致胚胎-胎儿危害当给予至一位妊娠妇女。在动物生殖研究中，gilteritinib给予至妊娠大鼠器官形成期的期间致胚胎-胎儿致死率，抑制胎儿生长和致畸胎性在母体暴露(AUC24)接近0.4倍AUC24在患者接受推荐剂量。 忠告生殖潜能的女性使用有效避孕用XOSPATA治疗期间和XOSPATA末次剂量后共至少 6个月。忠告有生殖潜能的女性伴侣的男性使用有效避孕用XOSPATA治疗期间和XOSPATA的末次剂量后共至少4个月。妊娠妇女，患者成为妊娠当接受XOSPATA或男性患者有妊娠女性伴侣应被忠告对胎儿的潜在风险[见在特殊人群中使用(8.1，8.3)和临床药理学(12.1)]。
6 不良反应
在说明书其他处描述以下严重的不良反应:
• 后可逆性脑病[见警告和注意事项(5.1)]
• 延长的QT间期[见警告和注意事项(5.2)]
6.1 临床试验经验
因为临床试验是在广泛地变化条件下进行，一个药物在临床试验中观察到的不良反应率不能被直接地与另一个药物在临床试验中的率比较和可能不反映在实践中观察到的率。
XOSPATA的安全性评价是根据 292患者有复发的或难治的AML用120 mg gilteritinib每天治疗。至XOSPATA 暴露的中位时间为3个月(范围0.1至 42.8月)。. 
在患者被报道的最频非血液学严重的不良反应(≥5%)为肺炎(19%)，脓毒血症(13%)，发热(13%)，呼吸困难(7%)和肾受损(5%)。
总体，2/292患者(8%)永久地终止XOSPATA治疗由于一个不良反应。最常见不良反应(>1%)导致终止为肺炎(2%)，脓毒血症(2%)和呼吸困难(1%)。最常见不良反应(≥20%)为肌肉痛/关节炎(42%)，转氨酶增加(41%)，疲乏/无力(40%)，发热(35%)，非感染腹泻(34%)，呼吸困难(34%)，水肿(34%)，皮疹(30%)，肺炎(30%)，恶心(27%)，口炎(26%)，咳嗽(25%)，头痛(21%)，低血压(21%)，眩晕(20%) 和呕吐(20%)。
 



其他临床上重要不良反应发生在≤10%的者包括心电图QT延长(7%)，心衰* (4%)，心包积液(3%)，心包炎(2%)，分化综合证(1%)，过敏反应(1%)和后部可逆性脑病综合 (1%).
*分组项目: 心衰，充血性心衰，心肌病变，心脏肥大，慢性左心室衰竭和射血分量减低。在表3中显示选择性基线后实验室数值被观察在有复发的或难治的AML患者。
 
7 药物相互作用
7.1其他药物对XOSPATA的影响 ，
组合的P-gp和强CYP3A诱导剂  XOSPATA与一种组合的 P-gp的同时使用，强 CYP3A诱导剂减低gilteritinib暴露它可能减低XOSPATA疗效[见临床药理学(12.3)]。避免XOSPATA 与组合 P-gp和强 CYP3A诱导剂的同时使用。
强CYP3A抑制剂
XOSPATA与一种强 CYP3A抑制剂的同时使用增加gilteritinib 暴露[见临床药理学(12.3)]。 开率另外治疗不是强CYP3A抑制剂。如这些抑制剂的同时使用被考虑对患者医护是必要的，更频繁地监视对XOSPATA不良反应。中断和减低XOSPATA剂量在患者有严重的或危及生命毒性[见剂量和给药方法(2.3)]。
7.2 XOSPATA对其他药物的影响 
靶向 5HT2B受体或Sigma非特异性受体药物gilteritinib的同时使用可能减低靶向5HT2B受体或sigma非特异性受体药物的效应(如，依他普仑[escitalopram]，氟西汀[fluoxetine]，舍曲林[sertraline])。避免这些药物与XOSPATA同时使用除非它们的使用被认为对患者的医护是必要的[见临床药理学(12.3)]。
8 在特殊人群中使用
8.1 妊娠 
风险总结
根据来自动物研究发现(见数据)和它的作用机制，XOSPATA可能致胎儿危害当给予至一位妊娠妇女[见临床药理学(12.1)]。
关于在妊娠妇女XOSPATA使用没有可得到数据告知一个药物-关联不良发育结局的风险。在动物生殖研究中，gilteritinib的给予至妊娠大鼠器官形成期的期间致不良发育结局包括胚胎-胎儿致死率，抑制胎儿生长，和致畸胎性在母体暴露(AUC24)接近0.4倍AUC24患者接受推荐剂量(见数据)。
忠告妊娠妇女对一个胎儿潜在风险。不良结局在妊娠发生不管母体的健康或药物的使用。
不知道对适应证人群重大出生缺陷和流产的背景风险。在美国一般人群，重大出生缺陷和在临床上认可妊娠中流产的估算背景风险分别是2%-4%和15 %。
数据
动物数据
在大鼠中一项胚胎-胎儿发育研究，妊娠动物接受口服剂量的gilteritinib为0，0.3，3，10，和30 mg/kg/day在器官形成的阶段期间。母体发现在30 mg/kg/day(导致在暴露接近0.4倍AUC24在患者接受推荐剂量)包括减低体重和食耗量。Gilteritinib的给药在剂量30mg/kg/day还致胚胎-胎儿死亡(植入后丢失)，减低胎儿体和胎盘重量，和减低骨化的胸骨的数目和骶和尾椎，和增加胎儿大体外部的发生率(全身性，局部水肿，露脑畸形，裂唇，腭裂，短尾，和脐疝)，内脏(小眼畸形; 心房和/或心室缺；和畸形/缺乏肾，和错位的肾上腺，和卵巢)，和骨骼(熊骨裂，缺乏肋骨，融合肋，融合的颈弓，不对齐的颈椎，和缺乏胸椎)异常。单次口服给予[14C] gilteritinib至妊娠 大鼠导致放射性转移至胎儿相似于在母体血浆中观察到在怀孕天14。此外，在大多数母体组织中放射性的分布图形和 胎儿在怀孕的天18是相似于怀孕的天14。
8.2 哺乳
风险总结
对gilteritinib和/或它的代谢物在人乳汁中的存在对哺乳喂养儿童的影响，或对乳汁产生的影响没有数据。放射性标记的gilteritinib的给予至哺乳大鼠后，乳汁放射性的浓度死较高于在母体血浆在4和24小时给药后。在动物研究中，gilteritinib和/或它的代谢物被分布至组织在婴儿大鼠通过乳汁。因为潜能对严重的不良反应在一只哺乳喂养儿童，建议一位哺乳妇女治疗期间用XOSPATA和末次给药后共2月不要哺乳喂养。
8.3 生殖潜能的女性和男性
妊娠测试
推荐对生殖潜能开始XOSPATA治疗前七天内妊娠测试[见在特殊人群中使用(8.1)]。
避孕
女性
忠告生殖潜能的女性治疗期间和XOSPATA末次剂量后共至少 6个月使用有效避孕。. 
男性
建议生殖潜能男性治疗期间和XOSPATA的末次剂量后共至少4个月使用有效避孕。
8.4 儿童使用
尚未确定在儿童患者中安全性和有效性。
8.5 老年人使用
在292患者XOSPATA的临床研究中，41%为年龄65岁或以上，而13%为75岁或以上。患者年龄65岁或以上和较年轻患者间未观察到在有效性或安全性中总体差别。
11 描述
Gilteritinib是一种酪氨酸激酶抑制剂。化学名为2-Pyrazinecarboxamide，6-ethyl-3-[[3-methoxy-4-[4-(4methyl-1-piperazinyl)-1-piperidinyl] phenyl] amino]-5-[(tetrahydro-2H-pyran-4-yl) amino]-，(2E)-2-butenedioate (2:1)。分子量为1221.50和分子式为(C29H44N8O3)2·C4H4O4。结构式为:
 
Gilteritinib延胡索酸盐是一种浅黄至黄粉或晶体可少量溶解在水和非常少量溶于无水乙醇。
XOSPATA (gilteritinib)是作为片提供口服给药。每片含40 mg的gilteritinib活性成分作为游离碱 (相当于44.2 mg gilteritinib延胡索酸盐)。无活性成分为甘露醇，羟基丙基纤维素，低取代羟基丙基纤维素，硬脂酸镁，羟丙甲纤维素，滑石，聚乙二醇，二氧化钛和氧化铁。.
12 临床药理学
12.1 作用机制
Gilteritinib是一种小分子抑制多种受体酪氨酸激酶，包括FMS-样酪氨酸激酶3 (FLT3)。Gilteritinib 显示抑制FLT3受体信号能力和外源地表达FLT3 包括FLT3-ITD，酪氨酸激酶结构域突变(TKD) FLT3-D835Y和FLT3-ITD-D835Y细胞增殖，和它诱导表达FLT3-ITD白血病细胞凋亡。
12.2 药效动力学 
在有复发的或难治的AML患者给予gilteritinib 120 mg， FLT3 磷酸化实质上(>90%)的抑制作用是迅速(首次剂量后24小时内)和持续，如同在一项体外体内血浆抑制活性(PIA)分析确定其特征。.
心脏电生理学
患者一天1次XOSPATA 120 mg对 QTc间期的影响曾被评价，它显示在QTc间期一个缺乏巨大均数增加(如，20 msec)。
在临床试验中，用 gilteritinib在120 mg测试的292被治疗患者中，4患者(1.4%)经历一个QTcF >500 msec。此外，跨越所有剂量，2.4%的复发/难治的受试者有一个最大基线后QTcF间期 >500 msec[见警告和注意事项(5.2)]。
12.3 药代动力学 
给予gilteritinib 120 mg每天1次后观察到以下药代动力学参数，除非另外说明。  
Gilteritinib暴露(Cmax和AUC24)正比例地增加随每天1次剂量范围从20 mg至450 mg (0.17至 3.75倍推荐剂量)在患者有复发的或难治的AML。Gilteritinib均数(±SD)稳态Cmax为374 ng/mL (±190)和AUC24为6943 ng•hr/mL (±3221)。在给药15天内达到稳态血浆水平与一个接近10-倍积蓄。
吸收
在空腹状态，观察到至最大gilteritinib浓度时间(tmax)是接近给药后4和6小时间。 
食物的影响
在健康成年给予一个单次gilteritinib 40 mg剂量(0.3 倍推荐剂量)，gilteritinib Cmax减低26%和AUC 减低低于10%当与一个高-脂肪餐共同给药(接近800至1,000总卡路里与500至600脂肪卡路里，250碳水化合物卡路里，150蛋白卡路里)与一个空腹状态比较。当 gilteritinib与一个高-脂肪餐被给予，中位数tmax被延迟2小时。 
分布
表观中央和周边分布容积的群体均数(%CV)估算值分别为1092 L (9.22%)和1100 L (4.99%)，它可能表明广发组织分布。在体内，gilteritinib是接近94%结合至人血浆蛋白。在体外，gilteritinib是主要结合至人血清白蛋白。 
消除
Gilteritinib的估算半衰期为113小时，而估算的表观清除率为14.85 L/h。
代谢
在体外，Gilteritinib是主要地通过CYP3A4被代谢。在稳态时，主要代谢物在人中包括M17 (通过N-去烷基化作用和氧化形成)，M16和M10 (两者通过N-烷基化作用形成)。做这些三个代谢物没有一个超过总体母体暴露的10%。
排泄
一个单次放射性标记剂量后，gilteritinib在粪便被排泄有总给药剂量的gilteritinib的总放射性标记的64.5%给药剂量在粪中被回收。16.4%作为未变化药物和代谢物在尿中被回收。
特殊人群
年龄(20-87岁)，性别，种族，轻度(Child-Pugh类别 A)或中度(Child-Pugh类别B) 肝受损和轻度 (肌酐清除率(CLCr) 50-80 mL/min)或中度(CLCr 30-50 mL/min)肾受损对gilteritinib的药代动力学没有临床意义的影响。不知道严重肝(Child-Pugh类别 C)或严重肾受损(CLCr ≤ 29 mL/min)对 gilteritinib药代动力学的影响。
药物相互作用研究
临床研究
P-gp和强 CYP3A诱导剂联用: Gilteritinib Cmax减低接近30%和AUC减低接近70%当与利福平[rifampin]共同给药(一种组合P-gp和强CYP3A诱导剂)。
强 CYP3A抑制剂:
Gilteritinib Cmax增加接近20%和AUC增加接近120%当共同给药与伊曲康唑[itraconazole](一种强 CYP3A抑制剂).
中度CYP3A抑制剂: 
Gilteritinib Cmax增加接近16%和AUC增加接近40%当共同给药与氟康唑[fluconazole] (一种中度 CYP3A 抑制剂).
CYP3A底物
咪达唑仑[Midazolam](一种CYP3A底物) Cmax和AUC增加接近10%当共同给药与gilteritinib。
MATE1底物: 
头孢氨苄[Cephalexin] (一种MATE1底物) Cmax和AUC减低低于10%当共同给药与gilteritinib。
体外研究
Gilteritinib抑制人5HT2B受体或sigma非特异性受体，它可能减低靶向这些受体例如依他普仑，氟西汀，舍曲林药物的效应。
Gilteritinib是一种P-gp转运蛋白的底物和有潜能抑制乳癌耐药蛋白(BCRP)和有机阳离子转运蛋白1 (OCT1)转运者.
13 非临床毒理学 
13.1 癌发生，突变发生，生育力受损 
未曾用gilteritinib进行致癌性研究。
在一种细菌致突变性(Ames)分析Gilteritinib没有致突变性和不是致畸变的在一项染色体畸变测试分析在中国仓鼠肺细胞。Gilteritinib是阳性在小鼠骨髓细胞微核的诱导从65 mg/kg (195 mg/m2)中点测试剂量(接近2.6倍推荐人剂量120 mg)。不知道XOSPATA对人生育力的影响。在狗中给予10 mg/kg/day gilteritinib在4-周研究(给药12天)导致生殖细胞退行性变性和坏死和睾丸精细胞聚细胞形成以及附睾头附睾管上皮单个细胞坏死。
13.2 动物毒理学和/或药理学 
在13-周口服重复给药毒性研究在大鼠和犬，毒性靶向器官包括眼和肾。
14 临床研究
14.1 复发的或难治的急性髓性白血病
XOSPATA的疗效被评估在ADMIRAL试验(NCT02421939)，包括138 成年患者有复发的或难治的AML有一个FLT3 ITD，D835，或I836突变被LeukoStrat CDx FLT3突变分析。临床试验包括患者来自以下种族: 60%白种人，27%亚裔，7%黑仲人或非洲美国人，1%土著夏威夷或其他太平洋岛民，1%其他和3%未知。XOSPATA被给予口服在一个开始剂量120 mg每天直至不嫩接受的毒性或缺乏临床获益。被允许剂量减低以处理不良事件，和剂量增加被允许，以增加临床获益。在表4中显示其他基线人口统计和疾病特征。
 
在ADMIRAL试验中疗效的确定是基于完全缓解(CR)/完全缓解与部分血液学恢复(CRh)的率，CR/CRh(DOR)的时间，和从输注依赖至输注无关的转换率。中位随访为4.6月(95% CI: 2.8，15.8)。. 14患者是仍在缓解在首次中期DOR分析的时候。疗效结果被显示在表5。对患者达到一个CR/CRh，至首次反应中位时间为3.6月(范围，0.9至9.6月)。CR/CRh率为29/126患者用FLT3-ITD或FLT3-ITD/TKD和0/12在患者仅用FLT3-TKD。106患者被依赖红细胞(RBC)和/或血小板输注在基线时，33(31.1%)变成不依赖RBC和血小板输注在基线后阶段任何56-天。对32患者在基线时RBC和血小板输注，17(53.1%)仍输注-无关在基线后阶段任何56-天期间。
 
16 如何供应/贮存和处置 
16.1 如何供应
XOSPATA (gilteritinib)40 mg片被作为浅黄，圆形，膜-包衣片凹陷有Astellas标记和‘235’在相同侧。XOSPATA片是可得到在乙酰包装大小:
• 90片有防儿童闭合瓶，(NDC 0469-1425-90)
16.2 贮存
贮存XOSPATA片在20ºC至25ºC(68°F至77°F); 外出允许15ºC至30ºC(59°F至86°F)[见USP控制室温]。保存在原始小瓶中。
17 患者咨询资料 
建议患者阅读FDA-批准的患者说明书(患者资料)。.
后部可逆性脑病综合征
忠告患者发生后部可逆性脑病综合征(PRES)的风险。要求患者立即地报告任何症状提示PRES，例如癫痫和改变的精神状态，至他们的卫生保健提供者为进一步评价[见警告和注意事项(5.1)]。
延长的QT间期
建议患者咨询他们的卫生保健提供者立即如他们感觉头晕，丧失意识，或有体征或症状提示性心律失常。建议有低钾血症或低镁血症病史患者，监视他们的电解质的重要性[见警告和注意事项(5.2)]。
胰腺炎
建议患者胰腺炎的风险和联系他们的卫生保健提供者对胰腺炎体征或症状，其中包括严重和持久胃痛，有或无恶心和呕吐[见警告和注意事项(5.3)]。 
避孕药的使用
• 建议有生殖潜能女性患者使用有效避孕方法当接受XOSPATA和避免妊娠当用治疗和完成治疗后共6月。 
• 建议患者XOSPATA治疗期间在一个妊娠事件或如怀疑妊娠立即告知他们的卫生保健提供者。
• 忠告有生殖潜能的女性伴侣的男性使用有效避孕用XOSPATA治疗期间和XOSPATA的末次剂量后共至少4个月[见在特殊人群中使用(8.3)].
哺乳
建议妇女用XOSPATA治疗期间最后给药后共至少2月不要哺乳喂养[见在特殊人群中使用(8.2)]。
给药指导
• 建议患者不要破坏，压碎或咀嚼片但用一杯水整吞它们。
• 指导患者，如他们缺失一剂XOSPATA，尽可能在相同天马上服用它，和至少在下一次计划剂量前12小时和下一次计划给药前至少12小时，和返回至正常计划以下天。指导患者在12小时内不要服用2剂[见剂量和给药方法(2.2)]

 

 

Xospata

 

Generic Name: gilteritinib
Dosage Form: tablet

Medically reviewed by Drugs.com. Last updated on May 1, 2019.

WARNING: DIFFERENTIATION SYNDROME

Patients treated with Xospata have experienced symptoms of differentiation syndrome, which can be fatal or life-threatening if not treated. Symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, or renal dysfunction. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].

Indications and Usage for XospataRelapsed or Refractory Acute Myeloid Leukemia

Xospata is indicated for the treatment of adult patients who have relapsed or refractory acute myeloid leukemia (AML) with a FMS-like tyrosine kinase 3 (FLT3) mutation as detected by an FDA-approved test.

Xospata Dosage and AdministrationPatient Selection

Select patients for the treatment of AML with Xospata based on the presence of FLT3 mutations in the blood or bone marrow [see Clinical Studies (http://www.fda.gov/CompanionDiagnostics.

Recommended Dosage

The recommended starting dose of Xospata is 120 mg orally once daily with or without food. Response may be delayed. In the absence of disease progression or unacceptable toxicity, treatment for a minimum of 6 months is recommended to allow time for a clinical response.

Do not break or crush Xospata tablets. Administer Xospata tablets orally about the same time each day. If a dose of Xospata is missed or not taken at the usual time, administer the dose as soon as possible on the same day, and at least 12 hours prior to the next scheduled dose. Return to the normal schedule the following day. Do not administer 2 doses within 12 hours.

Dose Modification

Assess blood counts and blood chemistries, including creatine phosphokinase, prior to the initiation of Xospata, at least once weekly for the first month, once every other week for the second month, and once monthly for the duration of therapy. Perform electrocardiogram (ECG) prior to initiation of treatment with gilteritinib, on days 8 and 15 of cycle 1, and prior to the start of the next two subsequent cycles.

Interrupt dosing or reduce dose for toxicities as per Table 1.

Table 1: Dosage Modifications for Xospata-Related Toxicities*
* Grade 1 is mild, Grade 2 is moderate, Grade 3 is serious, Grade 4 is life-threatening.
Adverse Reaction	Recommended Action
Differentiation Syndrome	• If differentiation syndrome is suspected, administer systemic corticosteroids and initiate hemodynamic monitoring until symptom resolution and for a minimum of 3 days [see Warnings and Precautions (5.1)]. • Interrupt Xospata if severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroids [see Warnings and Precautions (5.1)]. • Resume Xospata when signs and symptoms improve to Grade 2* or lower.
Posterior Reversible Encephalopathy Syndrome	• Discontinue Xospata.
QTc interval greater than 500 msec	• Interrupt Xospata. • Resume Xospata at 80 mg when QTc interval returns to within 30 msec of baseline or less than or equal to 480 msec.
QTc interval increased by >30 msec on ECG on day 8 of cycle 1	• Confirm with ECG on day 9. • If confirmed, consider dose reduction to 80 mg.
Pancreatitis	• Interrupt Xospata until pancreatitis is resolved. • Resume Xospata at 80 mg.
Other Grade 3* or higher toxicity considered related to treatment.	• Interrupt Xospata until toxicity resolves or improves to Grade 1*. • Resume Xospata at 80 mg.

Dosage Forms and Strengths

Tablets: 40 mg as light yellow, round-shaped, film-coated tablets debossed with the Astellas logo and ‘235’ on the same side.

Contraindications

Xospata is contraindicated in patients with hypersensitivity to gilteritinib or any of the excipients. Anaphylactic reactions have been observed in clinical trials [see Adverse Reactions (6) and Description (11)].

Warnings and PrecautionsDifferentiation Syndrome

Of 319 patients treated with Xospata in the clinical trials, 3% experienced differentiation syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal if not treated. Symptoms of differentiation syndrome in patients treated with Xospata included fever, dyspnea, pleural effusion, pericardial effusion, pulmonary edema, hypotension, rapid weight gain, peripheral edema, rash, and renal dysfunction. Some cases had concomitant acute febrile neutrophilic dermatosis. Differentiation syndrome occurred as early as 2 days and up to 75 days after Xospata initiation and has been observed with or without concomitant leukocytosis. Of the 11 patients who experienced differentiation syndrome, 9 (82%) recovered after treatment or after dose interruption of Xospata.

If differentiation syndrome is suspected, initiate dexamethasone 10 mg IV every 12 hours (or an equivalent dose of an alternative oral or IV corticosteroid) and hemodynamic monitoring until improvement. Taper corticosteroids after resolution of symptoms and administer corticosteroids for a minimum of 3 days. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid treatment. If severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroids, interrupt Xospata until signs and symptoms are no longer severe [see Dosage and Administration (2.3)].

Posterior Reversible Encephalopathy Syndrome

Of 319 patients treated with Xospata in the clinical trials, 1% experienced posterior reversible encephalopathy syndrome (PRES) with symptoms including seizure and altered mental status. Symptoms have resolved after discontinuation of Xospata. A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI). Discontinue Xospata in patients who develop PRES [see Dosage and Administration (2.3) and Adverse Reactions (6.1)].

Prolonged QT Interval

Xospata has been associated with prolonged cardiac ventricular repolarization (QT interval). Of the 317 patients with a post-baseline QTc measurement on treatment with Xospata in the clinical trial, 1% were found to have a QTc interval greater than 500 msec and 7% of patients had an increase from baseline QTc greater than 60 msec. Perform electrocardiogram (ECG) prior to initiation of treatment with gilteritinib, on days 8 and 15 of cycle 1, and prior to the start of the next two subsequent cycles. Interrupt and reduce Xospata dosage in patients who have a QTcF >500 msec [see Dosage and Administration (2.3), Adverse Reactions (6.1) and Clinical Pharmacology (12.2)].

Hypokalemia or hypomagnesemia may increase the QT prolongation risk. Correct hypokalemia or hypomagnesemia prior to and during Xospata administration.

Pancreatitis

Of 319 patients treated with Xospata in the clinical trials, 4% experienced pancreatitis. Evaluate patients who develop signs and symptoms of pancreatitis. Interrupt and reduce the dose of Xospata in patients who develop pancreatitis [see Dosage and Administration (2.3)].

Embryo-Fetal Toxicity

Based on findings in animals and its mechanism of action, Xospata can cause embryo-fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of gilteritinib to pregnant rats during organogenesis caused embryo-fetal lethality, suppressed fetal growth and teratogenicity at maternal exposures (AUC24) approximately 0.4 times the AUC24 in patients receiving the recommended dose. Advise females of reproductive potential to use effective contraception during treatment with Xospata and for at least 6 months after the last dose of Xospata. Advise males with female partners of reproductive potential to use effective contraception during treatment with Xospata and for at least 4 months after the last dose of Xospata. Pregnant women, patients becoming pregnant while receiving Xospata or male patients with pregnant female partners should be apprised of the potential risk to the fetus [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].

Adverse Reactions

The following clinically significant adverse reactions are described elsewhere in the labeling:

•

Differentiation syndrome [see Boxed Warning and Warnings and Precautions (5.1)]

•

Posterior reversible encephalopathy syndrome [see Warnings and Precautions (5.2)]

•

Prolonged QT interval [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 profile of Xospata is based on 319 patients with relapsed or refractory AML treated with gilteritinib 120 mg daily in three clinical trials. The median duration of exposure to Xospata was 3.6 months (range 0.1 to 43.4 months).

Fatal adverse reactions occurred in 2% of patients receiving Xospata. These included cardiac arrest (1%) and one case each of differentiation syndrome and pancreatitis. The most frequent (≥5%) nonhematological serious adverse reactions reported in patients were fever (13%), dyspnea (9%), renal impairment (8%), transaminase increased (6%) and noninfectious diarrhea (5%).

Of the 319 patients, 91 (29%) required a dose interruption due to an adverse reaction; the most common adverse reactions leading to dose interruption were aspartate aminotransferase increased (6%), alanine aminotransferase increased (6%) and fever (4%). Twenty patients (6%) required a dose reduction due to an adverse reaction. Twenty-two (7%) discontinued Xospata treatment permanently due to an adverse reaction. The most common (>1%) adverse reactions leading to discontinuation were aspartate aminotransferase increased (2%) and alanine aminotransferase increased (2%).

Overall, for the 319 patients, the most frequent (≥10%) all-grade nonhematological adverse reactions reported in patients were transaminase increased (51%), myalgia/arthralgia (50%), fatigue/malaise (44%), fever (41%), mucositis (41%), edema (40%), rash (36%), noninfectious diarrhea (35%), dyspnea (35%), nausea (30%), cough (28%), constipation (28%), eye disorders (25%), headache (24%), dizziness (22%), hypotension (22%), vomiting (21%), renal impairment (21%), abdominal pain (18%), neuropathy (18%), insomnia (15%) and dysgeusia (11%). The most frequent (≥5%) grade ≥3 nonhematological adverse reactions reported in patients were transaminase increased (21%), dyspnea (12%), hypotension (7%), mucositis (7%), myalgia/arthralgia (7%), and fatigue/malaise (6%). Shifts to grades 3-4 nonhematologic laboratory abnormalities included phosphate decreased 42/309 (14%), alanine aminotransferase increased 41/317 (13%), sodium decreased 37/314 (12%), aspartate aminotransferase increased 33/317 (10%), calcium decreased 19/312 (6%), creatine kinase increased 20/317 (6%), triglycerides increased 18/310 (6%), creatinine increased 10/316 (3%), and alkaline phosphatase increased 5/317 (2%).

Adverse reactions reported in the first 30 days of therapy on the ADMIRAL Study [see Clinical Studies (14)] are shown in Tables 2 and 3, according to whether patients were preselected for high intensity or low intensity chemotherapy.

Table 2: Adverse Reactions Reported in ≥10% (Any Grade) or ≥5% (Grade 3-5)* of Patients with Relapsed or Refractory AML in the Pre-selected High Intensity Chemotherapy Subgroup in the First 30 Days of the ADMIRAL Trial
* Grade 3-5 includes serious, life-threatening and fatal adverse reactions † Grouped terms: arthralgia, back pain, bone pain, flank pain, limb discomfort, medial tibial stress syndrome, myalgia, muscle twitching, musculoskeletal discomfort, musculoskeletal pain, muscle spasms, neck pain, non-cardiac chest pain, pain and pain in extremity ‡ Grouped terms: aspartate aminotransferase increased, alanine aminotransferase increased, blood alkaline phosphatase increased, gamma-glutamyltransferase increased, hepatic enzyme increased, hepatic function abnormal, hepatoxicity, liver function test increased and transaminases increased § Grouped terms: asthenia, fatigue, lethargy and malaise ¶ Grouped terms: edema, edema peripheral, face edema, fluid overload, generalized edema, hypervolemia, localized edema, periorbital edema and swelling face # Grouped terms: aphthous ulcer, colitis, enteritis, esophageal pain, gingival pain, large intestinal ulcer, laryngeal inflammation, lip blister, lip ulceration, mouth hemorrhage, mouth ulceration, mucosal inflammation, oral discomfort, oral pain, oropharyngeal pain, proctalgia, stomatitis, swollen tongue, tongue discomfort and tongue ulceration Þ Grouped terms: abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper and gastrointestinal pain ß Grouped terms: acne, dermatitis bullous, dermatitis contact, drug eruption, eczema asteatotic, erythema, hyperkeratosis, lichenoid keratosis, palmar-plantar erythrodysesthesia syndrome, rash, rash maculo-papular, rash papular, skin exfoliation, skin lesion and skin hyperpigmentation à Grouped terms: acute respiratory distress syndrome, dyspnea, dyspnea exertional, hypoxia, pulmonary edema, respiratory failure, tachypnea and wheezing è Grouped terms: hyperesthesia, hypoesthesia, neuralgia, neuropathy peripheral, peripheral sensory neuropathy and paresthesia ð Grouped terms: coordination abnormal and dizziness
Adverse Reaction	Any Grade n (%)		Grade ≥3 n (%)
	Xospata (120 mg daily) n=149	Chemotherapy n=68	Xospata (120 mg daily) n=149		Chemotherapy n=68
Musculoskeletal and connective tissue disorders
Myalgia/arthralgia†	56 (38)	20 (29)	1 (1)		3 (4)
Investigations
Transaminase increased‡	46 (31)	11 (16)	15 (10)		5 (7)
General disorders and administration site conditions
Fatigue/malaise§	36 (24)	9 (13)	1 (1)		2 (3)
Fever	25 (17)	21 (31)	2 (1)		4 (6)
Edema¶	20 (13)	13 (19)	0		0
Gastrointestinal disorders
Constipation	29 (20)	10 (15)	0		0
Mucositis#	18 (12)	30 (44)	0		5 (7)
Nausea	23 (15)	26 (38)	0		0
Abdominal painÞ	16 (11)	16 (24)	0		0
Blood and lymphatic system disorder
Febrile neutropenia	26 (17)	30 (44)	26 (17)		30 (44)
Skin and subcutaneous tissue disorders
Rashß	23 (15)	21 (31)	1 (1)		2 (3)
Respiratory, thoracic and mediastinal disorders
Dyspneaà	20 (13)	9 (13)	1 (1)		6 (9)
Cough	18 (12)	5 (7)	1 (1)		0
Nervous system disorders
Neuropathyè	19 (13)	0	0		0
Dizzinessð	17 (11)	2 (3)	0		0
Headache	17 (11)	12 (18)	0		0
Table 3: Adverse Reactions Reported in ≥10% (Any Grade) or ≥5% (Grade 3-5)* of Patients with Relapsed or Refractory AML in the Pre-selected Low Intensity Chemotherapy Subgroup in the First 30 Days of the ADMIRAL Trial
* Grade 3-5 includes serious, life-threatening and fatal adverse reactions † Grouped terms: aspartate aminotransferase increased, alanine aminotransferase increased, blood alkaline phosphatase increased and transaminases increased ‡ Grouped terms: arthralgia, arthritis, back pain, limb discomfort, myalgia, muscle contracture, muscle spasms, myositis, non-cardiac chest pain, pain, pain in extremity and polyarthritis § Grouped terms: asthenia, fatigue and malaise ¶ Grouped terms: edema, face edema, localized edema, edema peripheral, peripheral swelling, periorbital edema, scrotal edema and swelling face # Grouped terms: colitis, mouth hemorrhage, mouth ulceration, mucosal inflammation, oropharyngeal pain, proctalgia, stomatitis, tongue discomfort and tongue ulceration Þ Grouped terms: acute respiratory failure, dyspnea, hypoxia and respiratory failure ß Grouped terms: dermatitis acneiform, dermatitis bullous, dermatitis exfoliative, erythema, rash, rash maculo-papular, rash papular, rosacea and skin ulcer
Adverse Reaction	Any Grade n (%)		Grade ≥3 n (%)
	Xospata (120 mg daily) n=97	Chemotherapy n=41	Xospata (120 mg daily) n=97	Chemotherapy n=41
Investigations
Transaminase increased†	35 (36)	6 (15)	9 (9)	1 (2)
Blood and lymphatic system disorder
Febrile neutropenia	26 (27)	5 (12)	25 (26)	5 (12)
Musculoskeletal and connective tissue disorders
Myalgia/arthralgia‡	21 (22)	7 (17)	2 (2)	0
General disorders and administration site conditions
Fatigue/malaise§	20 (21)	9 (22)	4 (4)	1 (2)
Edema¶	19 (20)	5 (12)	1 (1)	0
Fever	11 (11)	7 (17)	0	0
Gastrointestinal disorders
Mucositis#	19 (20)	7 (17)	1 (1)	1 (2)
Constipation	13 (13)	5 (12)	1 (1)	0
Diarrhea	12 (12)	2 (5)	0	0
Nausea	10 (10)	7 (17)	0	0
Respiratory, thoracic and mediastinal disorders
DyspneaÞ	11 (11)	2 (5)	3 (3)	2 (5)
Skin and subcutaneous tissue disorders
Rashß	10 (10)	2 (5)	2 (2)	0

Other clinically significant adverse reactions occurring in ≤10% of patients included: electrocardiogram QT prolonged (9%), hypersensitivity* (8%), pancreatitis* (5%), cardiac failure* (4%), pericardial effusion (4%), acute febrile neutrophilic dermatosis (3%), differentiation syndrome (3%), pericarditis/myocarditis* (2%), large intestine perforation (1%), and posterior reversible encephalopathy syndrome (1%).

*Grouped terms: cardiac failure (cardiac failure, cardiac failure congestive, cardiomegaly, cardiomyopathy, chronic left ventricular failure, and ejection fraction decreased), hypersensitivity (anaphylactic reaction, angioedema, dermatitis allergic, drug hypersensitivity, erythema multiforme, hypersensitivity, and urticaria), pancreatitis (amylase increased, lipase increased, pancreatitis, pancreatitis acute), pericarditis/myocarditis (myocarditis, pericardial hemorrhage, pericardial rub, and pericarditis).

Selected post-baseline laboratory values that were observed in patients with relapsed or refractory AML are shown in Table 4.

Table 4: Shifts to Grade 3-4 Laboratory Abnormalities in Patients with Relapsed or Refractory AML by Pre-selected High Intensity and Low Intensity Chemotherapy in the First 30 Days of the ADMIRAL Trial
	Pre-selected High Intensity Chemotherapy Subgroup		Pre-selected Low Intensity Chemotherapy Subgroup
	Xospata (120 mg daily)	Chemotherapy	Xospata (120 mg daily)	Chemotherapy
Alanine aminotransferase increased	7/149 (5%)	1/66 (2%)	7/95 (7%)	1/41 (2%)
Alkaline phosphatase increased	1/149 (1%)	0	0	0
Aspartate aminotransferase increased	8/149 (5%)	2/65 (3%)	5/95 (5%)	0
Calcium decreased	2/149 (1%)	3/65 (5%)	3/94 (3%)	0
Creatine kinase increased	1/149 (1%)	0	1/95 (1%)	0
Phosphatase decreased	4/144 (3%)	6/65 (9%)	4/93 (4%)	3/38 (8%)
Sodium decreased	7/148 (5%)	5/65 (8%)	6/93 (6%)	2/41 (5%)
Triglycerides increased	1/146 (1%)	0	2/94 (2%)	0

Drug Interactions7.1 Effect of Other Drugs on Xospata

Combined P-gp and Strong CYP3A Inducers

Concomitant use of Xospata with a combined P-gp and strong CYP3A inducer decreases gilteritinib exposure which may decrease Xospata efficacy [see Clinical Pharmacology (12.3)]. Avoid concomitant use of Xospata with combined P-gp and strong CYP3A inducers.

Strong CYP3A Inhibitors

Concomitant use of Xospata with a strong CYP3A inhibitor increases gilteritinib exposure [see Clinical Pharmacology (12.3)]. Consider alternative therapies that are not strong CYP3A inhibitors. If the concomitant use of these inhibitors is considered essential for the care of the patient, monitor patient more frequently for Xospata adverse reactions. Interrupt and reduce Xospata dosage in patients with serious or life-threatening toxicity [see Dosage and Administration (2.3)].

Effect of Xospata on Other Drugs

Drugs that Target 5HT2B Receptor or Sigma Nonspecific Receptor

Concomitant use of gilteritinib may reduce the effects of drugs that target the 5HT2B receptor or the sigma nonspecific receptor (e.g., escitalopram, fluoxetine, sertraline). Avoid concomitant use of these drugs with Xospata unless their use is considered essential for the care of the patient [see Clinical Pharmacology (12.3)].

USE IN SPECIFIC POPULATIONSPregnancy

Risk Summary

Based on findings from animal studies (see Data) and its mechanism of action, Xospata can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)].

There are no available data on Xospata use in pregnant women to inform a drug-associated risk of adverse developmental outcomes. In animal reproduction studies, administration of gilteritinib to pregnant rats during organogenesis caused adverse developmental outcomes including embryo-fetal lethality, suppressed fetal growth, and teratogenicity at maternal exposures (AUC24) approximately 0.4 times the AUC24 in patients receiving the recommended dose (see Data). Advise pregnant women of the potential risk to a fetus.

Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The background risk of major birth defects and miscarriage for the indicated population is unknown. In theU.S.general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.

Data

Animal Data

In an embryo-fetal development study in rats, pregnant animals received oral doses of gilteritinib of 0, 0.3, 3, 10, and 30 mg/kg/day during the period of organogenesis. Maternal findings at 30 mg/kg/day (resulting in exposures approximately 0.4 times the AUC24 in patients receiving the recommended dose) included decreased body weight and food consumption. Administration of gilteritinib at the dose of 30 mg/kg/day also resulted in embryo-fetal death (postimplantation loss), decreased fetal body and placental weight, and decreased numbers of ossified sternebrae and sacral and caudal vertebrae, and increased incidence of fetal gross external (anasarca, local edema, exencephaly, cleft lip, cleft palate, short tail, and umbilical hernia), visceral (microphthalmia; atrial and/or ventricular defects; and malformed/absent kidney, and malpositioned adrenal, and ovary), and skeletal (sternoschisis, absent rib, fused rib, fused cervical arch, misaligned cervical vertebra, and absent thoracic vertebra) abnormalities.

Single oral administration of [14C] gilteritinib to pregnant rats resulted in transfer of radioactivity to the fetus similar to that observed in maternal plasma on day 14 of gestation. In addition, distribution profiles of radioactivity in most maternal tissues and the fetus on day 18 of gestation were similar to that on day 14 of gestation.

Lactation

Risk Summary

There are no data on the presence of gilteritinib and/or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Following administration of radiolabeled gilteritinib to lactating rats, milk concentrations of radioactivity were higher than radioactivity in maternal plasma at 4 and 24 hours post-dose. In animal studies, gilteritinib and/or its metabolite(s) were distributed to the tissues in infant rats via the milk. Because of the potential for serious adverse reactions in a breastfed child, advise a lactating woman not to breastfeed during treatment with Xospata and for at least 2 months after the last dose.

Females and Males of Reproductive Potential

Pregnancy testing

Pregnancy testing is recommended for females of reproductive potential within seven days prior to initiating Xospata treatment [see Use in Specific Populations (8.1)].

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment and for at least 6 months after the last dose of Xospata.

Males

Advise males of reproductive potential to use effective contraception during treatment and for at least 4 months after the last dose of Xospata.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Of the 319 patients in clinical studies of Xospata, 43% were age 65 years or older, and 13% were 75 years or older. No overall differences in effectiveness or safety were observed between patients age 65 years or older and younger patients.

Xospata Description

Gilteritinib is a tyrosine kinase inhibitor. The chemical name is 2-Pyrazinecarboxamide, 6-ethyl-3-[[3-methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl] phenyl] amino]-5-[(tetrahydro-2H-pyran-4-yl) amino]-, (2E)-2-butenedioate (2:1). The molecular weight is 1221.50 and the molecular formula is (C29H44N8O3)2·C4H4O4. The structural formula is:

Gilteritinib fumarate is a light yellow to yellow powder or crystals that is sparingly soluble in water and very slightly soluble in anhydrous ethanol.

Xospata (gilteritinib) is provided as a tablet for oral administration. Each tablet contains 40 mg of gilteritinib active ingredient as free base (corresponding to 44.2 mg gilteritinib fumarate). The inactive ingredients are ferric oxide, hydroxypropyl cellulose, hypromellose, low-substituted hydroxypropyl cellulose, mannitol, magnesium stearate, talc, polyethylene glycol and titanium dioxide.

Xospata - Clinical PharmacologyMechanism of Action

Gilteritinib is a small molecule that inhibits multiple receptor tyrosine kinases, including FMS-like tyrosine kinase 3 (FLT3). Gilteritinib demonstrated the ability to inhibit FLT3 receptor signaling and proliferation in cells exogenously expressing FLT3 including FLT3-ITD, tyrosine kinase domain mutations (TKD) FLT3-D835Y and FLT3-ITD-D835Y, and it induced apoptosis in leukemic cells expressing FLT3-ITD.

Pharmacodynamics

In patients with relapsed or refractory AML administered gilteritinib 120 mg, substantial (>90%) inhibition of FLT3 phosphorylation was rapid (within 24 hours after first dose) and sustained, as characterized by an ex vivo plasma inhibitory activity (PIA) assay.

Cardiac Electrophysiology

The effect of Xospata 120 mg once a day on the QTc interval has been evaluated in patients, which showed an absence of large mean increases (i.e., 20 msec) in the QTc interval.

Of 317 patients with a post-baseline QTc measurement on treatment with gilteritinib at 120 mg in clinical trials, 4 patients (1.3%) experienced a QTcF >500 msec. Additionally, across all doses 2.3% of patients with relapse/refractory AML had a maximum post-baseline QTcF interval >500 msec [see Warnings and Precautions (5.3)].

Pharmacokinetics

The following pharmacokinetic parameters were observed following administration of gilteritinib 120 mg once daily, unless otherwise specified.

Gilteritinib exposure (Cmax and AUC24) increases proportionally with once daily doses ranging from 20 mg to 450 mg (0.17 to 3.75 times the recommended dosage) in patients with relapsed or refractory AML. Gilteritinib mean (±SD) steady-state Cmax is 374 ng/mL (±190) and AUC24 is 6943 ng•hr/mL (±3221). Steady-state plasma levels are reached within 15 days of dosing with an approximate 10-fold accumulation.

Absorption

The time to maximum gilteritinib concentration (tmax) observed is approximately between 4 and 6 hours postdose in the fasted state.

Effect of Food

In healthy adults administered a single gilteritinib 40 mg dose (0.3 times the recommended dosage), gilteritinib Cmax decreased by 26% and AUC decreased by less than 10% when co-administered with a high-fat meal (approximately 800 to 1,000 total calories with 500 to 600 fat calories, 250 carbohydrate calories, 150 protein calories) compared to a fasted state. Median tmax was delayed 2 hours when gilteritinib was administered with a high-fat meal.

Distribution

The population mean (%CV) estimates of apparent central and peripheral volume of distribution were 1092 L (9.22%) and 1100 L (4.99%), respectively, which may indicate extensive tissue distribution. In vivo, gilteritinib is approximately 94% bound to human plasma proteins. In vitro, gilteritinib is primarily bound to human serum albumin.

Elimination

The estimated half-life of gilteritinib is 113 hours, and the estimated apparent clearance is 14.85 L/h.

Metabolism

Gilteritinib is primarily metabolized via CYP3A4 in vitro. At steady state, the primary metabolites in humans include M17 (formed via N-dealkylation and oxidation), M16 and M10 (both formed via N‑dealkylation). None of these 3 metabolites exceeded 10% of overall parent exposure.

Excretion

After a single radiolabeled dose, gilteritinib is excreted in feces with 64.5% of the total administered dose recovered in feces. Of the total radiolabeled dose of gilteritinib, 16.4% was recovered in urine as unchanged drug and metabolites.

Specific Populations

Age (20-87 years), sex, race, mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment and mild (creatinine clearance (CLCr) 50-80 mL/min) or moderate (CLCr 30-50 mL/min) renal impairment do not have clinically meaningful effects on the pharmacokinetics of gilteritinib.

The effect of severe hepatic (Child-Pugh Class C) or severe renal impairment (CLCr ≤ 29 mL/min) on gilteritinib pharmacokinetics is unknown.

Drug Interaction Studies

Clinical Studies

Combined P-gp and Strong CYP3A Inducers:

Gilteritinib Cmax decreased approximately 30% and AUC decreased approximately 70% when co-administered with rifampin (a combined P-gp and strong CYP3A inducer).

Strong CYP3A Inhibitors:

Gilteritinib Cmax increased approximately 20% and AUC increased approximately 120% when co-administered with itraconazole (a strong CYP3A inhibitor).

Moderate CYP3A Inhibitors:

Gilteritinib Cmax increased approximately 16% and AUC increased approximately 40% when co-administered with fluconazole (a moderate CYP3A inhibitor).

CYP3A Substrates:

Midazolam (a CYP3A substrate) Cmax and AUC increased approximately 10% when co-administered with gilteritinib.

MATE1 Substrates:

Cephalexin (a MATE1 substrate) Cmax and AUC decreased by less than 10% when co-administered with gilteritinib.

In Vitro Studies

Gilteritinib inhibits human 5HT2B receptor or sigma nonspecific receptors, which may reduce the effects of drugs that target these receptors such as escitalopram, fluoxetine and sertraline.

Gilteritinib is a substrate of P-gp transporter and has the potential to inhibit breast cancer resistance protein (BCRP) and organic cation transporter 1 (OCT1) transporters.

Nonclinical ToxicologyCarcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been performed with gilteritinib.

Gilteritinib was not mutagenic in a bacterial mutagenesis (Ames) assay and was not clastogenic in a chromosome aberration test assay in Chinese hamster lung cells. Gilteritinib was positive for the induction of micronuclei in mouse bone marrow cells from 65 mg/kg (195 mg/m2) the mid dose tested (approximately 2.6 times the recommended human dose of 120 mg).

The effect of Xospata on human fertility is unknown. Administration of 10 mg/kg/day gilteritinib in the 4-week study in dogs (12 days of dosing) resulted in degeneration and necrosis of germ cells and spermatid giant cell formation in the testis as well as single cell necrosis of the epididymal duct epithelia of the epididymal head.

Animal Toxicology and/or Pharmacology

In the 13-week oral repeated dose toxicity studies in rats and dogs, target organs of toxicity included the eye and kidney.

Clinical StudiesRelapsed or Refractory Acute Myeloid Leukemia

The efficacy of Xospata was assessed in the ADMIRAL Trial (NCT02421939), which included adult patients with relapsed or refractory AML having a FLT3 ITD, D835, or I836 mutation by the LeukoStrat® CDx FLT3 Mutation Assay. Xospata was given orally at a starting dose of 120 mg daily until unacceptable toxicity or lack of clinical benefit.

First Interim Analysis

The efficacy of Xospata was established on the basis of the rate of complete remission (CR)/CR with partial hematological recovery (CRh), the duration of CR/CRh (DOR), and the rate of conversion from transfusion dependence to transfusion independence at the first interim analysis in the ADMIRAL trial (n=138). The median follow-up was 4.6 months (95% CI: 2.8, 15.8). Fourteen patients were still in remission at the time of the first interim DOR analysis. The efficacy results are shown in Table 5. For patients who achieved a CR/CRh, the median time to first response was 3.6 months (range, 0.9 to 9.6 months). The CR/CRh rate was 29 of 126 in patients with FLT3-ITD or FLT3-ITD/TKD and 0 of 12 in patients with FLT3-TKD only.

Among the 106 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 33 (31.1%) became independent of RBC and platelet transfusions during any 56-day post-baseline period. For the 32 patients who were independent of both RBC and platelet transfusions at baseline, 17 (53.1%) remained transfusion-independent during any 56-day post-baseline period.

Table 5: Efficacy Results in Patients with Relapsed or Refractory AML Treated with Xospata in the First Interim Analysis (ADMIRAL Trial)
CI: confidence interval; NE: not estimable; NR: not reached; Only responses prior to HSCT were included in response rate.
* CR was defined as an absolute neutrophil count ≥1.0 x 109/L, platelets ≥100 x 109/L, normal marrow differential with <5% blasts, must have been red blood cells, platelet transfusion independent and no evidence of extramedullary leukemia. † CRh was defined as marrow blasts <5%, partial hematologic recovery absolute neutrophil count ≥0.5 x 109/L and platelets ≥50 x 109/L, no evidence of extramedullary leukemia and could not have been classified as CR. ‡ The 95% CI rate was calculated using the exact method based on binomial distribution. § DOR was defined as the time from the date of either first CR or CRh until the date of a documented relapse of any type. Deaths were counted as events. ¶ Response was ongoing.
Remission Rate	Xospata N=138
CR*/CRh† n/N (%)	29/138 (21)
95% CI‡	14.5, 28.8
Median DOR§ (months)	4.6
Range (months)	0.1 to 15.8¶
CR* n/N (%)	16/138 (11.6)
95% CI‡	6.8, 18.1
Median DOR§ (months)	8.6
Range (months)	1 to 13.8
CRh† n/N (%)	13/138 (9.4)
95% CI‡	5.1, 15.6
Median DOR§ (months)	2.9
Range (months)	0.1 to 15.8¶

Final Analysis

The final analysis of the ADMIRAL trial included 371 adult patients randomized 2:1 to receive Xospata 120 mg once daily (n=247) over continuous 28-day cycles or a prespecified chemotherapy regimen (n=124). Randomization was stratified by response to first-line AML therapy and prespecified chemotherapy. The prespecified chemotherapy regimens included high intensity combinations (MEC and FLAG-IDA) and low intensity regimens (LDAC and AZA).

The demographic and disease characteristics of the randomized patients are shown in Table 6.

Table 6: Baseline Demographic and Disease Characteristics in Patients with Relapsed or Refractory AML in the Final Analysis (ADMIRAL Trial)
AML: acute myeloid leukemia; FLT3: FMS-related tyrosine kinase 3; ITD: internal tandem duplication; TKD: D835/I836 tyrosine kinase domain point mutation; ECOG PS: Eastern Cooperative Oncology Group performance status; CRc: Composite complete remission (complete remission [CR] + complete remission with incomplete hematologic recovery [CRi] + complete remission with incomplete platelet recovery [CRp]); HSCT: Hematopoietic stem cell transplantation
* Patients were defined as transfusion dependent at baseline if they were dosed and received any red blood cell or platelet transfusions within the 56-day baseline period. † Prior use of FLT3 inhibitor is defined as “Yes” if patients received prior AML therapy of midostaurin, sorafenib or quizartinib; otherwise, prior use of FLT3 inhibitor was assigned as “No.” ‡ MEC: mitoxantrone 8 mg/m2, etoposide 100 mg/m2 and cytarabine 1000 mg/m2 once daily by IV for 5 days § FLAG-IDA: granulocyte colony-stimulating factor 300 mcg/m2 once daily by SC days 1 to 5, fludarabine 30 mg/m2 once daily by IV days 2 through 6, cytarabine 2000 mg/m2 once daily by IV for days 2 through 6, idarubicin 10 mg/m2 once daily by IV days 2 through 4 ¶ LDAC: cytarabine 20 mg twice daily by subcutaneous (SC) or intravenous (IV) for 10 days # AZA: azacitidine 75 mg/m2 once daily by SC or IV for 7 days
Demographic and Disease Characteristics	Xospata (120 mg daily) N=247	Chemotherapy N=124
Demographics
Median Age (Years) (Range)	62 (20, 84)	62 (19, 85)
Age Categories, n (%)
<65 years	141 (57)	75 (60)
≥65 years	106 (43)	49 (40)
Sex, n (%)
Male	116 (47)	54 (44)
Female	131 (53)	70 (57)
Race, n (%)
White	145 (59)	75 (60)
Asian	69 (28)	33 (27)
Black or African American	14 (6)	7 (6)
Native Hawaiian or Other Pacific Islander	1 (0.4)	0
Other	5 (2)	1 (0.8)
Unknown/Missing	13 (5)	8 (6)
Baseline ECOG, n (%)
0-1	206 (83)	105 (85)
≥2	41 (17)	19 (15)
Disease Characteristics
Untreated relapse AML, n (%)	151 (61)	74 (60)
Primary refractory AML, n (%)	96 (39)	49 (40)
Refractory relapse AML, n (%)	0	1 (0.8)
Number of Relapses, n (%)
0	96 (39)	49 (40)
1	149 (60)	74 (60)
2 or more	2 (0.8)	1 (0.8)
Median number of relapses (Range)	1 (0, 2)	1 (0, 2)
Transfusion Dependent at Baseline, n (%)*	197 (80)	97 (89)
FLT3 Mutation Status, n (%)
ITD alone	215 (87)	113 (91)
TKD alone	21 (9)	10 (8)
ITD and TKD	7 (3)	0
Prior Use of FLT3 Inhibitor†, n (%)
No	215 (87)	110 (89)
Yes	32 (13)	14 (11)
Prespecified Chemotherapy
High Intensity	149 (60)	75 (60)
MEC‡	-	33 (27)
FLAG-IDA§	-	42 (34)
Low Intensity	98 (40)	49 (40)
LDAC¶	-	17 (14)
AZA#	-	32 (26)

The final analysis included an assessment of OS, measured from the date of randomization until death by any cause. At the time of analysis, median follow-up was 17.8 months (range, 14.9 to 19.1). Patients randomized to the Xospata arm had significantly longer survival compared to the chemotherapy arm (HR 0.64; 95% CI: 0.49 – 0.83; 1-sided p-value: 0.0004). Figure 1 and Table 7 show the results of the OS analysis.

Exploratory subgroup analyses demonstrated that the hazard ratio for survival was 0.66 (95% CI: 0.47 – 0.93) for patients in the high intensity chemotherapy stratum and 0.56 (95% CI: 0.38 – 0.84) for patients in the low intensity chemotherapy stratum. The CR rates are shown in Table 7. For patients on Xospata and chemotherapy arms, the CR rates were 15.4% (95% CI: 10% – 22.3%) and 16% (95% CI: 8.6% – 26.3%), respectively, for patients in the high intensity chemotherapy stratum, and 12.2% (95% CI: 6.5% – 20.4%) and 2% (95% CI 0.1% – 10.9%), respectively, for patients in the low intensity chemotherapy stratum.

Table 7: OS and CR* in Patients with Relapsed or Refractory AML in the Final Analysis (ADMIRAL Trial)
CI: confidence interval; Only responses prior to HSCT were included in response rate.
* CR was defined as an absolute neutrophil count ≥1.0 x 109/L, platelets ≥100 x 109/L, normal marrow differential with <5% blasts, must have been red blood cells, platelet transfusion independent and no evidence of extramedullary leukemia. † The 95% CI rate was calculated using the exact method based on binomial distribution. ‡ DOR was defined as the time from the date of first remission until the date of a documented relapse.
	Xospata N=247	Chemotherapy N=124
Overall Survival
Deaths, n (%)	171 (69.2%)	90 (72.6%)
Median in months (95% CI)	9.3 (7.7, 10.7)	5.6 (4.7, 7.3)
Hazard Ratio (95% CI)	0.64 (0.49, 0.83)
p-value (1-sided)	0.0004
Complete Remission
CR, n (%)	35 (14.2%)	13 (10.5%)
(95% CI† )	(10.1, 19.2)	(5.7, 17.3)
Median DOR‡ (range) (months)	14.8 (0.6 to 23.1+)	1.8 (<0.1+ to 1.8)

Figure 1: Kaplan-Meier Plot of Overall Survival in ADMIRAL Trial

In the final analysis, the CR/CRh rate in the gilteritinib arm was 22.6% (55/243) and the DOR was 7.4 months (range, <0.1+ to 23.1+). For patients who achieved a CR/CRh, the median time to first response was 2 months (range, 0.9 to 9.6 months). The CR/CRh rate was 49 of 215 in patients with FLT3-ITD only, 3 of 7 in patients with FLT3-ITD/TKD and 3 of 21 in patients with FLT3-TKD only.

Among the 197 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 68 (34.5%) became independent of RBC and platelet transfusions during any 56-day post-baseline period. For the 49 patients who were independent of both RBC and platelet transfusions at baseline, 29 (59.2%) remained transfusion-independent during any 56-day post-baseline period.

How Supplied/Storage and HandlingHow Supplied

Xospata (gilteritinib) 40 mg tablets are supplied as light yellow, round-shaped, film-coated tablets debossed with the Astellas logo and ‘235’ on the same side. Xospata tablets are available in the following package size:

•

Bottles of 90 tablets with Child Resistant Closure, (NDC 0469-1425-90)

Storage

Store Xospata tablets at 20ºC to 25ºC (68°F to 77°F); excursions permitted between 15ºC to 30ºC (59°F to 86°F) [See USP Controlled Room Temperature]. Keep in original container until dispensed. Protect from light, moisture and humidity.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Differentiation Syndrome

Advise patients of the risks of developing differentiation syndrome as early as 2 days after the start of therapy and during the first 3 months on treatment. Ask patients to immediately report any symptoms suggestive of differentiation syndrome, such as fever, cough or difficulty breathing, rash, low blood pressure, rapid weight gain, swelling of their arms or legs, or decreased urinary output, to their healthcare provider for further evaluation [see Boxed Warning and Warnings and Precautions (5.1)].

Posterior Reversible Encephalopathy Syndrome

Advise patients of the risk of developing posterior reversible encephalopathy syndrome (PRES). Ask patients to immediately report any symptoms suggestive of PRES, such as seizure and altered mental status, to their healthcare provider for further evaluation [see Warnings and Precautions (5.2)].

Prolonged QT Interval

Advise patients to consult their healthcare provider immediately if they feel faint, lose consciousness, or have signs or symptoms suggestive of arrhythmia. Advise patients with a history of hypokalemia or hypomagnesemia of the importance of monitoring their electrolytes [see Warnings and Precautions (5.3)].

Pancreatitis

Advise patients of the risk of pancreatitis and to contact their healthcare provider for signs or symptoms of pancreatitis, which include severe and persistent stomach pain, with or without nausea and vomiting [see Warnings and Precautions (5.4)].

Use of Contraceptives

•

Advise female patients with reproductive potential to use effective contraceptive methods while receiving Xospata and to avoid pregnancy while on treatment and for 6 months after completion of treatment.

•

Advise patients to notify their healthcare provider immediately in the event of a pregnancy or if pregnancy is suspected during Xospata treatment.

•

Advise males with female partners of reproductive potential to use effective contraception during treatment with Xospata and for at least 4 months after the last dose of Xospata [see Use in Specific Populations (8.3)].

Lactation

Advise women not to breastfeed during treatment with Xospata for at least 2 months after the final dose [see Use in Specific Populations (8.2)].

Dosing Instructions

•

Advise patients not to break, crush or chew the tablets but to swallow them whole with a cup of water.

•

Instruct patients that, if they miss a dose of Xospata, to take it as soon as possible on the same day, and at least 12 hours prior to the next scheduled dose, and return to the normal schedule the following day. Instruct patients to not take 2 doses within 12 hours [see Dosage and Administration (2.2)].

Distributed by:
Astellas Pharma US, Inc.
Northbrook, Illinois 60062

Xospata® is a registered trademark of Astellas Pharma Inc.
LeukoStrat® is a registered trademark of Invivoscribe, Inc.
©2019 Astellas Pharma US, Inc.
222317-GLT

MEDICATION GUIDE Xospata® (Zoh spah' tah) (gilteritinib) tablets
What is the most important information I should know about Xospata? Xospata may cause serious side effects, including: Differentiation Syndrome. Differentiation syndrome is a condition that affects your blood cells and may be life-threatening or lead to death if not treated. Differentiation syndrome can happen as early as 2 days after starting Xospata and during the first 3 months of treatment. Call your healthcare provider or go to the nearest hospital emergency room right away if you develop any of the following symptoms of differentiation syndrome while taking Xospata:
o fever o cough o trouble breathing o rash		o dizziness or lightheadedness o rapid weight gain o swelling of your arms or legs o decreased urination
If you develop any of these symptoms of differentiation syndrome, your healthcare provider may treat you with a corticosteroid medicine and may monitor you in the hospital. See “What are the possible side effects of Xospata?” for more information about side effects.
What is Xospata? Xospata is a prescription medicine used to treat adults with acute myeloid leukemia (AML) who have a FMS-like tyrosine kinase 3 (FLT3) mutation: • when the disease has come back, or • has not improved after previous treatment(s). Your healthcare provider will perform a test to make sure that Xospata is right for you. It is not known if Xospata is safe and effective in children.
Who should not take Xospata? Do not take Xospata if you are allergic to gilteritinib or any of the ingredients in Xospata. See the end of this Medication Guide for a complete list of ingredients in Xospata.
Before taking Xospata, tell your healthcare provider about all of your medical conditions, including if you: • have any heart problems, including a condition called long QT syndrome. • have problems with abnormal electrolytes such as sodium, potassium, or magnesium levels. • are pregnant or plan to become pregnant. Xospata can cause harm to your unborn baby. You should avoid becoming pregnant during treatment with Xospata. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with Xospata. o If you are able to become pregnant, your healthcare provider may perform a pregnancy test 7 days before you start treatment with Xospata. o Females who are able to become pregnant should use effective birth control (contraception) during treatment with Xospata and for at least 6 months after the last dose of Xospata. o Males who have female partners that are able to become pregnant should use effective birth control (contraception) during treatment with Xospata and for at least 4 months after the last dose of Xospata. • are breastfeeding or plan to breastfeed. It is not known if Xospata passes into your breast milk. Do not breastfeed during treatment with Xospata and for at least 2 months after the last dose of Xospata. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
How should I take Xospata? • Take Xospata exactly as your healthcare provider tells you to. Do not change your dose or stop taking Xospata without talking to your healthcare provider. • Take Xospata 1 time a day at about the same time each day. • Swallow Xospata tablets whole. Do not break, crush, or chew the tablet. • Xospata can be taken with or without food. • If you miss a dose of Xospata, or did not take it at the usual time, take your dose as soon as possible and at least 12 hours before your next dose. Return to your normal schedule the following day. Do not take 2 doses of Xospata within 12 hours.
What are the possible side effects of Xospata? Xospata may cause serious side effects, including: • See “What is the most important information I should know about Xospata?” • Posterior Reversible Encephalopathy Syndrome (PRES). If you take Xospata, you may be at risk of developing a condition involving the brain called PRES. Tell your healthcare provider right away if you have a seizure or quickly worsening symptoms such as headache, decreased alertness, confusion, reduced eyesight, blurred vision, or other visual problems. Your healthcare provider will do a test to check for PRES. Your healthcare provider will stop Xospata if you develop PRES. • Changes in the electrical activity of your heart called QTc prolongation. QTc prolongation can cause irregular heartbeats that can be life-threatening. Your healthcare provider will check the electrical activity of your heart with a test called an electrocardiogram (ECG) before you start taking Xospata and during your treatment with Xospata. Tell your healthcare provider right away if you feel dizzy, lightheaded, or faint. The risk of QT prolongation is higher in people with low blood magnesium or low blood potassium levels. Your healthcare provider will do blood tests to check your potassium and magnesium levels before and during your treatment with Xospata. • Inflammation of the pancreas (pancreatitis). Tell your healthcare provider right away if you have severe stomach (abdomen) pain that does not go away. This pain may happen with or without nausea and vomiting. The most common side effects of Xospata include:
o changes in liver function tests o joint or muscle pain o tiredness o fever o pain or sores in mouth or throat o swelling of arms or legs	o rash o diarrhea o shortness of breath o nausea o cough o constipation		o eye problems o headache o dizziness o low blood pressure o vomiting o decreased urination
Your healthcare provider may tell you to decrease your dose, temporarily stop, or completely stop taking Xospata if you develop certain side effects during treatment with Xospata. These are not all of the possible side effects of Xospata. 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 Xospata? • Xospata comes in a child-resistant package. • Store Xospata at room temperature between 68°F to 77°F (20°C to 25°C). • Keep Xospata in the original container provided by your pharmacist to protect it from light, moisture and humidity. • Keep Xospata and all medicines out of the reach of children.
General information about the safe and effective use of Xospata. Medicines are sometimes prescribed for conditions not listed in a Medication Guide. Do not use Xospata for a condition for which it was not prescribed. Do not give Xospata to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about Xospata that is written for healthcare professionals.
What are the ingredients in Xospata? Active ingredient: gilteritinib Inactive ingredients: ferric oxide, hydroxypropyl cellulose, hypromellose, low-substituted hydroxypropyl cellulose, mannitol, magnesium stearate, talc, polyethylene glycol and titanium dioxide. Distributed by: Astellas Pharma US, Inc., Northbrook, Illinois 60062 Xospata® is a registered trademark of Astellas Pharma Inc. ©2019 Astellas Pharma US, Inc. For more information about Xospata, call 1-800-727-7003, or visit www.Xospata.com. 222317-GLT

This Medication Guide has been approved by the U.S. Food and Drug Administration.                                             Issued: May 2019

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL – 40 mg Tablet Bottle Carton

NDC 0469-1425-90

Xospata®
(gilteritinib) tablets
40 mg

Do not break, crush or chew tablets.

90 tablets

Rx only

Xospata  gilteritinib tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0469-1425 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength GILTERITINIB FUMARATE (GILTERITINIB) GILTERITINIB 40 mg

Inactive Ingredients Ingredient Name Strength MANNITOL   HYDROXYPROPYL CELLULOSE, UNSPECIFIED   LOW-SUBSTITUTED HYDROXYPROPYL CELLULOSE, UNSPECIFIED   MAGNESIUM STEARATE   HYPROMELLOSE, UNSPECIFIED   TALC   POLYETHYLENE GLYCOL, UNSPECIFIED   TITANIUM DIOXIDE   FERRIC OXIDE RED

Product Characteristics Color YELLOW (Light yellow) Score no score Shape ROUND Size 7mm Flavor Imprint Code Logo;235 Contains

Packaging # Item Code Package Description 1 NDC:0469-1425-90 1 BOTTLE in 1 CARTON 1 90 TABLET in 1 BOTTLE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA211349 11/29/2018

Labeler - Astellas Pharma US, Inc. (605764828)

 

Astellas Pharma US, Inc.