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简介：   商品名：Sylvant 通用名：siltuximab 审批分类：优先审评+孤儿药 活性成分：siltuximab。 药品介绍 强生（JNJ）旗下杨森-Cilag国际（Janssen-Cilag International）近日宣布，欧盟委员会（EC）已批准单抗药物Sylvant（siltuximab），用于HIV阴性和人类疱疹病毒-8（HHV-8）阴性的多中心型巨大淋巴结增生症（multicentric Castleman'sdisease，MCD）患者的治疗。Sylvant是欧盟批准的首个MCD治疗药物。 Sylvant是一种单克隆抗体，是IL-6拮抗剂，通过静脉输注给药，每3周一次，该药已于2014年4月获FDA批准用于相同适应症，也是FDA批准的首个MCD治疗药物。Sylvant通过靶向白介素6（IL-6）发挥作用，IL-6似乎是MCD的关键驱动因子。 Sylvant的疗效和安全性，已在一项关键性III期研究（MCD2001）中得到证实。该研究是首个在MCD患者中开展的随机III期研究，评价了siltuximab+最佳支持治疗（BSC）相对于安慰剂+BSC治疗MCD患者的疗效和安全性。研究数据表明，siltuximab+BSC治疗组有显着更多的患者取得了持续的肿瘤和对症响应（肿瘤体积减少和疾病症状减轻）（34%vs0%，p=0.0012）。 多中心型巨大淋巴结增生症（MCD）是一种罕见疾病，是由于某种类型的白细胞过度生产导致淋巴结肿大。该病可能导致各种症状，并削弱免疫系统，使之难以对抗感染。对MCD患者而言，感染会非常严重甚至可能致命。目前，在美国和欧洲，还没有药物获批用于治疗这种罕见血液疾病。 强生于2013年9月向FDA和欧洲药品管理局（EMA）提交了siltuximab治疗MCD的生物制品许可申请（BLA）和上市许可申请（MAA），此前，FDA和EMA均已授予siltuximab治疗MCD的孤儿药地位。 关于Sylvant（siltuximab）： siltuximab是一种实验性、抗白介素6（IL-6）嵌合单克隆抗体，靶向并结合人IL-6。IL-6是由多种细胞产生的一种多功能细胞因子，如T细胞、B细胞、单核细胞、成纤维细胞和内皮细胞。MCD疾病的发病机制，牵涉受影响的淋巴结中活化B细胞内IL-6的失调或不平衡过量生产。 注射用Sylvant(siltuximab)使用说明书2014年第一版    批准日期：April 22，2014年4月22日；公司：Janssen Research & Development，LLC   FDA药物评价和研究中心血液学和肿瘤学产品室主任Richard Pazdur，医学博士说：“Sylvant 是有MCD治疗患者首个被FDA-批准药物，”“今天批准证实 FDA对罕见疾病药物批准的承诺。” 优先审评孤儿产品   处方资料重点  这些重点不包括安全和有效使用SYLVANT 所需所有资料。请参阅SYLVANT™完整处方资料。  注射用SYLVANT(siltuximab)，为静脉输注   适应证和用途 SYLVANT是一种白介素-6(IL-6)拮抗剂适用为有多中心Castleman氏病(MCD)人免疫缺陷病毒(HIV)阴性和人类疱疹病毒-8 (HHV-8)阴性患者的治疗。 (1)  没有在HIV阳性或HHV-8阳性有MCD患者研究SYLVANT使用的限制，因为在一项非临床研究中SYLVANT不与病毒产生的IL-6结合。 剂量和给药方法 只为静脉输注。通过历时1小时静脉输注给予11 mg/kg剂量每3周。 (2)  剂型和规格 ⑴在一个单次使用小瓶中100 mg冻干粉。 (3)  ⑵在一个单次使用小瓶中400 mg冻干粉。 (3)  禁忌证 对 siltuximab或任何SYLVANT中赋形剂严重超敏反应。(4)  警告和注意事项 ⑴ 当前活动性严重感染  ⒈ 在感染解决前不要给予 SYLVANT至严重感染患者。(2)  ⒉ 对患者接受SYLVANT严密监视感染。开始及时抗感染治疗和不要给予SYLVANT直至感染解决。 (2)  ⑵免疫接种：不要给予活疫苗因为IL-6抑制作用可能干扰对新抗原的正常免疫反应。(5.2)  ⑶输注相关反应： 在提供复苏设备，药物，和受过提供复苏训练人员情况给予SYLVANT。 (6.1)  ⑷胃肠道(GI)穿孔：患者可能处于风险增加谨慎使用。及时评价存在可能与GI穿孔有关联或提示性症状患者。(5.4)  不良反应 在MCD临床试验中用SYLVANT治疗期间最常见不良反应(与安慰剂比较>10%)是瘙痒，体重增加，皮疹，高尿酸血症，和上呼吸道感染。 为报告怀疑不良反应，联系Janssen Biotech，Inc. 电话1-800-526-7736 (1-800-JANSSEN)或FDA电话1-800-FDA¬1088或www.fda.gov/medwatch. 完整处方资料 1 适应证和用途  SYLVANT适用为人免疫缺陷病毒(HIV)阴性和人类疱疹病毒-8(HHV-8)阴性多中心Castleman氏病(MCD)患者的治疗. 没有在HIV阳性或HHV-8阳性有MCD患者中研究SYLVANT的使用限制因为一项非临床研究中SYLVANT与病毒产生的IL-6不结合。 2 剂量和给药方法 2.1 剂量 历时1小时静脉输注给予SYLVANT 11 mg/kg每3周1次直至治疗失败。.  SYLVANT治疗对头12个月和其后每3个给药疗程每次给药前进行血液学实验室测试。如不符合表1中概述治疗标准，考虑延迟用SYLVANT治疗。不减低剂量。 直至感染解决前不给予SYLVANT至有严重感染患者。有严重输注相关反应，过敏性反应，严重过敏反应，或细胞因子释放综合征患者终止SYLVANT。不再开始治疗。 2.2 为配制和给药指导  用无菌术为重建和制备给药溶液。 ⒈计算重建的SYLVANT溶液需要的剂量(mg)，总体积(mL)和小瓶数。建议用一个21-号1-½英寸针为制备。输注袋(250 mL)必须含5%葡萄糖水溶液和必须用聚氯乙烯(PVC)与二-{2-乙基己基邻苯二甲酸酯}(DEHP)，或聚烯烃(PO)制造。 ⒉让小瓶SYLVANT至室温历时约30分钟。为制备期间SYLVANT应保持在室温。 ⒊如表2指导所示无菌重建每一个SYLVANT小瓶。 轻轻旋转重建小瓶有助于溶解冻干粉。不要剧烈摇晃或旋转。在所有固体完全溶解前不要取内容物。冻干粉应在少于60分钟溶解。 一旦重建，和进一步稀释前，观察小瓶有无颗粒和变色。如存在颗粒或溶液变色或如明显不透明不要使用。重建产品加入输注袋前保存不应超过两小时。 ⒋通过从5%葡萄糖水250 mL袋抽吸溶液等同与计算重建SYLVANT总体积用无菌5%葡萄糖水稀释重建的SYLVANT溶液至250 mL。缓慢加重建SYLVANT溶液总计算体积(mL)至5%葡萄糖水输注袋。轻轻倒置袋混合溶液。 ⒌通过历时1小时期间静脉输注给予稀释5%葡萄糖水250 mL的SYLVANT溶液利用用聚氯乙析(PVC)与二-{2-乙基己基邻苯二甲酸酯}(DEHP) 或聚氨酯(PU)衬里的给药组件线，含一个 0.2µ 内联聚醚砜(PES)滤膜。应在4小时内完成重建稀释输注袋。 ⒍不要在输注SYLVANT相同的静脉线同时用其他药物。 ⒎不要贮存任何未用重建产品或输注溶液。应按照局部要求遗弃废物料。 3 剂型和规格  可得到如下注射用SYLVANT(siltuximab)： 为静脉输注在一个单次使用小瓶中100 mg冻干粉。 为静脉输注在一个单次使用小瓶中400 mg冻干粉。 4 禁忌证  对siltuximab或SYLVANT中任何赋形剂严重超敏反应。 5 警告和注意事项 5.1 当前活动性严重感染  对有严重感染患者在感染解决前不要给予SYLVANT。SYLVANT可能掩盖急性炎症体征和症状包括发热和急性期反应物抑制例如C-反应性蛋白(CRP)。接受SYLVANT患者严密监视感染。开始及时抗感染治疗和感染解决前不要进一步给予SYLVANT。  5.2 免疫接种  接受SYLVANT患者不要给予活疫苗因为IL-6抑制作用可能干扰对新抗原正常免疫反应。 5.3 输注相关反应和超敏性  如患者发生过敏性反应的体征停止输注SYLVANT。终止进一步用SYLVANT治疗。 如患者发生轻至中度输注反应停止输注。如反应解决，可能在较低输注速率再开始SYLVANT输注。考虑用抗组织胺，对乙酰氨基酚[acetaminophen]，和皮质激素。如这些干预后患者不能耐受输注终止SYLVANT[见不良反应(6)]。 在环境提供复苏仪器，药物，和受过复苏训练人员下给予SYLVANT。 5.4 胃肠道穿孔  在临床试验中曾报道胃肠道(GI)穿孔尽管不是在MCD试验。在可能处于GI穿孔风险增加患者中谨慎试验。患者存在GI穿孔关联或提示性症状及时评价。 6 不良反应 说明书另外节中更详细讨论下列不良反应： ●同时活动性严重感染[见警告和注意事项(5.1)]  ●输注-相关反应和超敏性[见警告和注意事项(5.3)]  6.1 临床试验经验 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。 在MCD临床试验中用SYLVANT治疗期间最常见不良反应(与安慰剂比较>10%)是瘙痒，体重增加，皮疹，高尿酸血症，和上呼吸道感染。 在下面表3展示来自研究1收集的数据。研究1，在MCD中，是一项国际，多中心，随机化2期 研究每3周输注比较SYLVANT和最佳支持性护理(BSC)与安慰剂和BSC。有53例患者随机化至SYLVANT臂剂量11 mg/kg和26患者随机化至安慰剂臂。在26例安慰剂-治疗患者中，13例患者随后被交叉至接受SYLVANT。中位年龄为48岁(范围20至78)，66%男性，48%亚裔，39% 白种人，4% 黑种人或非洲美国人，7%其他。随机化至SYLVANT患者接受中位19次输注(范围1至50)与之比较随机化至安慰剂患者接受中位8次输注(范围2至32)。为控制臂间不同暴露，表 3报道每患者在头8次输注后期间不良反应发生率。SYLVANT臂被展示发生>3%不良反应。 在研究2中在另一种血液病中作为单药评价SYLVANT。研究2是一项国际，多中心，随机化2期研究每4周输注比较SYLVANT和BSC与安慰剂和BSC。有50例患者随机化至SYLVANT臂剂量15 mg/kg (未被批准剂量)和26例患者随机化至安慰剂臂。中位年龄为72 岁(范围50至85)，58%男性，96%白种人，1%亚裔，1%黑种人，1%其他。两组输注中位次数为3(范围1至4)。由于缺乏疗效研究早期停止。表4展示SYLVANT臂发生>3%不良反应。 长期暴露  在研究3中评价患有MCD者长期给予SYLVANT的安全性。研究3纳入来自初始剂量发现研究有MCD从慢性SYLVANT治疗获益患者。SYLVANT被给予剂量11 mg/kg每3至6周。. 在数据截止时纳入19例患者。中位年龄为44岁(范围18 - 76)，63%男性，84%高加索人，11% 亚裔，和5%黑种人。这些 19例患者对SYLVANT中位暴露为5.1年(范围3.4至7.2)。在本研究中接受SYLVANT受试者报道最常见不良反应(>20%)为上呼吸道感染(63%)；腹泻(32%); 肢体疼痛，关节痛和疲乏(各21%)。没有患者为任何理由离开治疗。没有死亡。延长用SYLVANT治疗没有鉴定到累积毒性. 过敏性反应和输注相关反应  约750例患者曾用SYLVANT治疗。这些其中，1例患者经受过敏反应。来自249例用SYLVANT治疗患者单药治疗数据形成输注相关反应安全性评价的基础。这些患者4.8%报道输注相关反应。输注反应症状由背痛，胸痛或不适，恶心和呕吐，脸红，红斑，和心悸组成。 免疫原性  免疫原性数据是高度依赖于所用测试方法的灵敏度和特异性。另外，一个测试方法观察到阳性发生率可能手几种因素影响，包括样品处置，采样时间，药物干扰，同时用药和所患疾病。因此，对SYLVANT抗体的发生率与对其他产品抗体发生率的比较可能是误导。不知道用SYLVANT治疗后抗-siltuximab抗体的临床意义。 曾利用抗原桥接酶免疫分析(EIA)和基于电化学发光免疫分析(ECLIA)方法评价siltuximab的免疫原性。跨越临床试验总共411例患者在多个时间点评价用SYLVANT治疗对siltuximab对抗治疗抗体(ATA)反应。SYLVANT给药后，0.2%(1/411)患者对抗-siltuximab测试阳性。单个阳性样品进一步免疫原性分析揭示低滴度抗isiltuximab抗体有非-中和能力。 在发生对siltuximab抗体患者中没有鉴定出改变毒性图形的证据。 7 药物相互作用 未曾用SYLVANT 进行体外或体内药物-药物相互作用研究， 7.1 细胞色素P450底物  肝中细胞色素P450s被感染和炎症刺激包括细胞因子例如IL-6向下调节。用SYLVANT治疗患者中IL-6信号的抑制作用可能恢复CYP450活性至较高水平导致CYP450底物的药物代谢比用SYLVANT治疗前增加。 正在被有狭窄治疗指数CYP450底物治疗患者中SYLVANT的开始或终止，需要时进行治疗性监视影响(如，华法林[warfarin])或药物浓度如，环孢素[cyclosporine]或茶碱[theophylline])和调整剂量。在停止治疗后SYLVANT对CYP450酶活性的影响可能持续几周。当SYLVANT谨慎对待与CYP3A4底物药物共同给药其不想要的有效性减低时(如，口避孕药，洛伐他汀[lovastatin]，阿托伐他汀[atorvastatin])。 8 在特殊人群中使用  8.1 妊娠  妊娠类别C  风险-总结  在妊娠妇女中没有适当或对照良好研究。在动物生殖研究中，给予siltuximab至妊娠的食蟹猴致妊娠动物中和在子代中球蛋白水平减低。在猴中Siltuximab穿越过胎盘。用siltuximab治疗的妊娠妇女出生的婴儿可能是处在感染风险增加，而建议对这些婴儿给予活疫苗要谨慎小心。妊娠期间只有如潜在获益胜过对胎儿潜在风险时才应使用。忠告育婴潜能患者避免妊娠。育儿潜能妇女在治疗期间和治疗后3个月应使用避孕。 动物数据 在一项胚胎-胎儿发育研究中，在妊娠(GD)天第20至118天期间，包括器官形成期，静脉给予妊娠猴siltuximab剂量9.2或46 mg/kg/week。在GD 140，约天然出生前25天，评价胎儿。在低和高剂量第25次给予后暴露分别为人类推荐剂量11 mg/kg暴露的约3和7倍。没有siltuximab-相关母体或胎儿毒性，但是，在两个剂量siltuximab都穿越过胎盘和当在GD 140测量，胎儿siltuximab血清浓度与母体浓度相似。在一项联合胚胎胎儿和前-和后-新生儿发育研究中，食蟹猴在从GD 20至天然分娩(GD 167)被静脉给予剂量10或50 mg/kg/week对IL-6人抗体。在子代出生后至7个月被评价对发育的影响。未观察到母体或婴儿毒性；但是，在两种剂量，在妊娠动物(GD 34 至哺乳第30天) 和在子代(哺乳第 30-120天)球蛋白水平减低。 8.3 哺乳母亲  不知道siltuximab是否排泄在人乳汁中或摄入后被全身吸收。因为许多和免疫球蛋白被分泌在人乳汁中，和因为对哺乳婴儿来自SYLVANT不良反应潜能，应做出决策是否终止哺乳或终止药物，考虑药物对母亲的重要性。 8.4 儿童使用  尚未确定在儿童患者中SYLVANT的安全性和疗效。 8.5 老年人使用 在临床研究中用SYLVANT单药治疗患者127例(35%)为65岁和以上。这些患者和较年轻患者间未观察到安全性图形中总体差异，而报道的其他临床经验未曾确定老年人和较年轻患者安全性图形差别，但不能除外有限老年个体较大敏感性。临床研究未包括足够数量年龄65岁和以上患者不能确定在MCD人群中年龄对疗效的影响。 8.6 有肾受损患者  利用来自临床试验患者数据基于群体药代动力学分析，在预先-存在轻度至中度肾受损患者(肌酐清除率(CLCr) ≥15 mL/min)与基线正常肾功能(CLCr ≥90 mL/min)患者比较，未观察到siltuximab清除率显著差别。对有CLCr ≥15 mL/min患者无需调整初始剂量。不能确定肾病终末期对siltuximab药代动力学的潜在影响[见临床药理学(12.3)]。 8.7 有肝受损患者 利用来自临床试验患者数据基于群体药代动力学分析，在预先-存在轻度至中度肝受损患者(分别Child-Pugh类型A和B)与正常肝功能患者比较，观察到siltuximab清除率无显著差别。对轻度至中度肝受损患者无需剂量调整。临床试验未包括基线严重肝受损(Child-Pugh类别C)患者[见临床药理学(12.3)]。 10 药物过量 无药物过量病例报道。 11 一般描述  SYLVANT(siltuximab)是一个与人类白介素-6 (IL-6)结合的人-鼠嵌合单克隆抗体。通过中国仓鼠卵巢细胞生产SYLVANT。 SYLVANT以在单次使用小瓶中无菌，白色，无防腐剂，冻干粉供应。 每个SYLVANT 100 mg单次使用小瓶含100 mg siltuximab，3.7 mg L-组氨酸(来自L-组氨酸和L-组氨酸盐酸盐一水合物)，0.8 mg山梨醇80，和169 mg蔗糖。 每个SYLVANT 400 mg单次使用小瓶含400 mg siltuximab，14.9 mg L-组氨酸(来自L-组氨酸和L-组氨酸盐酸盐一水合物)，3.2 mg山梨醇80，和677 mg蔗糖。.  用无菌注射用水，USP (见2.2节)重建后，其pH约为5.2。得到溶液含20 mg/mL siltuximab稀释后通过静脉输注给药[见剂量和给药方法(2)].  12 临床药理学 12.1 作用机制 Siltuximab与人类IL-6结合和预防IL-6与可溶性和膜-结合IL-6受体两者的结合。曾被显示IL-6 在不同生理过程例如免疫球蛋白分泌有牵连。在有MCD患者中IL-6的过度产生与系统性表现有关联。.  12.2 药效动力学 心脏电生理：在一项开放，单臂研究在30有意义不明的单克隆丙种球蛋白病，阴燃多发性骨髓瘤，或惰性骨髓瘤患者中评价多剂量SYLVANT(15 mg/kg 每3周共4疗程)对QTc间期的影响。本研究为检测到均数QTc间期(即，>20 ms)巨大变化。 在治疗期间血清或血浆IL-6浓度的测量不应被用作为药效动力学标志，因为SYLVANT-被中和抗体-IL-6复合物干扰当前基于免疫学IL-6定量方法。  12.3 药代动力学  在有多中心Castleman氏病患者和血液学和非-血液学恶性病中评价siltuximab的药代动力学。 血清siltuximab的药代动力学被一个有一级消除的线性两-房室静脉模型适当地描述。 吸收 在有多中心Castleman氏病患者给予SYLVANT后(11 mg/kg，每3周1次历时1-小时静脉输注)，最大血清siltuximab浓度(Cmax)发生在接近输注结束。在稳态时，对siltuximab血清均数Cmax值是332 µg/mL(42% CV)，和血清给药前均数谷浓度值为84 µg/mL(78% CV)。 用每3周1次给药方案，在第6次输注时实现siltuximab稳态，和相对于单次给药siltuximab 积蓄 约1.7-倍。多次给药后，跨越2.8至11 mg/kg剂量范围siltuximab显示接近正比例药代动力学。 基于群体药代动力学分析，在一例体重70 kg男性受试者中央室分布容积为4.5 L (20% CV)。 消除 基于群体药代动力学分析，患者中siltuximab的清除是0.23 L/day(51% CV)。基于群体药代动力学分析(n=378)，体重被确定为对siltuximab清除唯一的统计显著的协变量。因此，基于体重给药是适当的。 患者首次静脉输注11 mg/kg后siltuximab均数末端半衰期(t1/2)是20.6天(范围：14.2至29.7 天).  特殊人群 年龄和性别  基于群体药代动力学分析，年龄[范围：18至85岁(n=378)]和性别[女性(n=175)，男性(n=203)]不影响siltuximab的暴露。 肾受损  来自纳入临床试验377例患者数据进行群体药代动力学分析(基于预先存在肾功能)，包括176例有正常肾功能(CLCr ≥90 mL/min)，122例有轻度肾受损 (CLCr 60至<90 mL/min)，75例有中度肾受损(CLCr 30至<60 mL/min)，和3例有严重肾受损(CLCr 15至29 mL/min)。在有预先存在轻，中度和严重肾受损患者(CLCr 15至<90 mL/min)与有正常肾功能患者比较siltuximab的表观清除率相似。不能确定肾病终末期对siltuximab 药代动力学潜在影响因为可得到的临床和药代动力学数据来自只有一例患者。 肝受损 来自纳入临床试验377例患者数据群体药代动力学分析(基于预先存在肝功能)，包括302例有正常肝功能，72例有轻度肝受损(Child-Pugh A)，和3 例有中度肝受损(Child-Pugh B)。有预先存在轻度和中度肝受损(Child-Pugh Class A和B)患者与正常肝功能患者比较siltuximab的表观清除率相似。不能确定严重肝受损对siltuximab药代动力学的潜在影响因为不能得到临床和药代动力学数据。 13 非临床毒理学  13.1 癌发生，突变发生s，生育力受损  没有用siltuximab进行致癌性或遗传毒性研究。 进行两项生育力研究。在一项研究，药物处理雄性小鼠与未处理雌性交配和在第二个研究药物处理雌性小鼠与未处理雄性交配。两项研究都用一个siltuximab的鼠同系物被皮下给予剂量至100 mg/kg/week总共7剂。对雄性或雌性生育力参数都没有影响。此外，在6个月重复给药毒理学研究中在剂量至siltuximab 46 mg/kg(患者在人推荐剂量全身暴露约7倍)在食蟹猴生殖器官中不产生任何毒性。 14 临床研究  研究1  在研究1，一项2期，多国家，随机化(2:1)双盲，安慰剂对照研究确定SYLVANT对有MCD患者的治疗的临床疗效和安全性。在这项研究中53例患者被随机化至最佳支持性护理(BSC)和SYLVANT在剂量11 mg/kg每3周和26例患者被随机化至BSC和安慰剂。中位年龄为48岁(范围20至78)，66%男性，48%亚裔，39%白种人，4%黑种人或非洲美国人，7%其他。两治疗臂中MCD组织学亚型相似，有33%透明血管亚型，23%浆细胞亚型和44%会合亚型。治疗继续直至治疗失败(被定义为根据症状，放射影像学进展或体能状态恶化疾病进展)或不能接受毒性。  研究的主要疗效结局为耐久肿瘤和症状反应，被定义为肿瘤反应(PR和CR基于国际工作组恶性淋巴瘤疗效改进的标准)由独立审评和完全解决或MCD症状稳定化。由研究者按照NCI-CTCAE版本4收集和分级34种被前瞻性鉴定的MCD相关症状。耐久反应被定义为肿瘤和症状性反应最少持续18周无治疗失败。在SYLVANT臂耐久肿瘤和症状反应34%与之比较安慰剂臂为0% (95% CI：11.1，54.8; p=0.0012)。 其他分析包括肿瘤反应，至治疗失败时间和在研究纳入时贫血患者在13周时血红蛋白增加1.5 g/dL或更多。总结结果见表5。 对亚组分析对所有被评价参数确证一致治疗效应除了透明血管组织学亚型。没有患者有透明血管组织学证实耐久肿瘤和症状反应。但是，活性提示在该亚型根据血红蛋白和至治疗失败中位时间变化。 在分析时间，总生存数据不成熟。SYLVANT臂中一年生存率为100%和安慰剂臂为92%。 16 如何供应/贮存和处置  16.1 如何供应  每个SYLVANT小瓶被个别地包装在一纸盒中： ●NDC 57894-420-01含一个100 mg小瓶，单次使用小瓶 ●NDC 57894-421-01含一个400 mg小瓶，单次使用小瓶 16.2 贮存和稳定性  SYLVANT必须在冰箱在2ºC至8ºC (36ºF至46ºF)。不要使用在纸盒和小瓶标记超出失效日期的SYLVANT。 当贮存时，避光保护。这个产品不含防腐剂。 17 患者咨询资料 见FDA-批准的患者说明书(患者资料)。 患者或其护理人员应被忠告SYLVANT的潜在获益和风险。 医生应指导其患者SYLVANT治疗开始前阅读患者说明书和每次接受输注再阅读它。在每次治疗访问评估患者总体健康很重要和来自患者或其护理人员阅读患者说明书讨论得到的任何问题。 告知患者SYLVANT可能降低他们对感染抗力。指导患者当症状提示出现感染时为了确保迅速评价和适当治疗立即联系其医生的重要性。 免疫接种 告知患者用SYLVANT治疗前他们应讨论建议的免疫接种。 过敏反应 忠告患者如输注期间经历任何严重过敏反应症状寻求立即医学关注。体征包括：呼吸困难，胸闷，喘息，严重眩晕或头晕，唇肿胀或皮肤皮疹。 避孕 忠告有生育潜能患者避免妊娠可能包括治疗期间和SYLVANT治疗后3个月使用避孕药。 其他医学条件 忠告患者报告任何新的或医学情况变坏。

Sylvant

Generic Name: siltuximab
Dosage Form: injection, powder, lyophilized, for solution

Medically reviewed on June 1, 2018

 

 

Indications and Usage for Sylvant

Sylvant is indicated for the treatment of patients with multicentric Castleman's disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative.

Limitations of Use

Sylvant was not studied in patients with MCD who are HIV positive or HHV-8 positive because Sylvant did not bind to virally produced IL-6 in a nonclinical study.

Sylvant Dosage and AdministrationDosage

Administer Sylvant 11 mg/kg over 1 hour as an intravenous infusion every 3 weeks until treatment failure.

Perform hematology laboratory tests prior to each dose of Sylvant therapy for the first 12 months and every 3 dosing cycles thereafter. If treatment criteria outlined in Table 1 are not met, consider delaying treatment with Sylvant. Do not reduce dose.

Table 1: Treatment Criteria
Laboratory parameter	Requirements before first Sylvant administration	Retreatment criteria
* Sylvant may increase hemoglobin levels in MCD patients
Absolute Neutrophil Count	≥1.0 × 109/L	≥1.0 × 109/L
Platelet count	≥75 × 109/L	≥50 × 109/L
Hemoglobin*	<17 g/dL	<17 g/dL

Do not administer Sylvant to patients with severe infections until the infection resolves.

Discontinue Sylvant in patients with severe infusion related reactions, anaphylaxis, severe allergic reactions, or cytokine release syndromes. Do not reinstitute treatment.

Instructions for Preparation and Administration

Use aseptic technique for reconstitution and preparation of dosing solution.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

1. Calculate the dose (mg), total volume (mL) of reconstituted Sylvant solution required and the number of vials needed. A 21-gauge 1½ inch needle is recommended for preparation. Infusion bags (250 mL) must contain Dextrose 5% in Water and must be made of polyvinyl chloride (PVC), or polyolefin (PO), or polypropylene (PP), or polyethylene (PE). Alternatively PE bottles may be used.

2. Allow the vial(s) of Sylvant to come to room temperature over approximately 30 minutes. Sylvant should remain at room temperature for the duration of the preparation.

3. Aseptically reconstitute each Sylvant vial as instructed in Table 2.

Table 2: Reconstitution Instructions
Strength	Amount of Sterile Water for Injection, USP required for reconstitution	Post-reconstitution concentration
100 mg vial	5.2 mL	20 mg/mL
400 mg vial	20 mL	20 mg/mL

Gently swirl the reconstituted vials to aid the dissolution of the lyophilized powder. DO NOT SHAKE or SWIRL VIGOROUSLY. Do not remove the contents until all of the solids have been completely dissolved. The lyophilized powder should dissolve in less than 60 minutes.

Once reconstituted, and prior to further dilution, inspect the vials for particulates and discoloration. Do not use if particles or solution discoloration are present or if visibly opaque. The reconstituted product should be kept for no more than two hours prior to addition into the infusion bag.

4. Dilute the reconstituted Sylvant solution dose to 250 mL with sterile Dextrose 5% in Water by withdrawing a volume equal to the total calculated volume of reconstituted Sylvant from the Dextrose 5% in Water, 250 mL bag. Slowly add the total calculated volume (mL) of reconstituted Sylvant solution to the Dextrose 5% in Water infusion bag. Gently invert the bag to mix the solution.

5. Administer the diluted Sylvant solution in 5% Dextrose in Water 250 mL by intravenous infusion over a period of 1 hour using administration sets lined with PVC, or polyurethane (PU), or PE, containing a 0.2-micron inline polyethersulfone (PES) filter. The infusion should be completed within 4 hours of the dilution of the reconstituted solution to the infusion bag.

6. Do not infuse Sylvant concomitantly in the same intravenous line with other agents.

7. Sylvant does not contain preservatives. Do not store any unused portion of the reconstituted product or of the infusion solution. Waste material should be disposed of in accordance with local requirements.

Dosage Forms and Strengths

Sylvant (siltuximab) for injection is available as:

100 mg of lyophilized powder in a single-dose vial for intravenous infusion.

400 mg of lyophilized powder in a single-dose vial for intravenous infusion.

Contraindications

Severe hypersensitivity reaction to siltuximab or any of the excipients in Sylvant [see Warnings and Precautions (5.3)]. Hypersensitivity reactions, including anaphylactic reaction, hypersensitivity, and drug hypersensitivity have been reported in patients treated with siltuximab.

Warnings and PrecautionsConcurrent Active Severe Infections

Do not administer Sylvant to patients with severe infections until the infection resolves. Sylvant may mask signs and symptoms of acute inflammation including suppression of fever and of acute Phase reactants such as C-reactive protein (CRP). Monitor patients receiving Sylvant closely for infections. Institute prompt anti-infective therapy and do not administer further Sylvant until the infection resolves.

Vaccinations

Do not administer live vaccines to patients receiving Sylvant because IL-6 inhibition may interfere with the normal immune response to new antigens.

Infusion Related Reactions and Hypersensitivity

Sylvant may cause infusion related reactions and anaphylaxis. Approximately 945 patients have been treated with Sylvant in clinical trials. Of these, one patient experienced an anaphylactic reaction. Data from 254 patients treated with Sylvant monotherapy forms the basis of the safety evaluation of infusion related reactions. Infusion related reactions were reported in 5.1% of these patients. Two (0.8%) were Grade 3 or higher, and 1 (0.4%) was serious; none were fatal. Symptoms of infusion reactions consisted of back pain, chest pain or discomfort, nausea and vomiting, flushing, erythema, and palpitations.

In long-term treatment of MCD patients with siltuximab at the recommended dosage of 11 mg/kg every 3 weeks, infusion related reactions or hypersensitivity reactions occurred at a frequency of 6.3% (1.3% for severe reactions).

Stop the infusion of Sylvant if the patient develops signs of anaphylaxis. Discontinue further therapy with Sylvant.

Stop the infusion if the patient develops a mild to moderate infusion reaction. If the reaction resolves, the Sylvant infusion may be restarted at a lower infusion rate. Consider medication with antihistamines, acetaminophen, and corticosteroids. Discontinue Sylvant if the patient does not tolerate the infusion following these interventions [see Adverse Reactions (6)].

Administer Sylvant in a setting that provides resuscitation equipment, medication, and personnel trained to provide resuscitation.

Gastrointestinal Perforation

Gastrointestinal (GI) perforation has been reported in clinical trials although not in MCD trials. Use with caution in patients who may be at increased risk for GI perforation. Promptly evaluate patients presenting with symptoms that may be associated or suggestive of GI perforation.

Adverse Reactions

The following adverse reactions are also discussed in other sections of the labeling:

· Concurrent active severe infections [see Warnings and Precautions (5.1)]

· Infusion-related reactions and hypersensitivity [see Warnings and Precautions (5.3)]

· Gastrointestinal perforation [see Warnings and Precautions (5.4)]

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 clinical practice.

Study 1, in MCD, was an international, multicenter, randomized Phase 2 study of every 3 week infusions comparing Sylvant and best supportive care (BSC) to placebo and BSC. There were 53 patients randomized to the Sylvant arm at a dosage of 11 mg/kg and 26 patients randomized to the placebo arm. Of the 26 placebo-treated patients, 13 patients subsequently crossed-over to receive Sylvant. The median age was 48 years (range 20 to 78), 66% male, 48% Asian, 39% White, 4% Black or African American, 7% other. The patients randomized to Sylvant received a median of 19 infusions (range 1 to 50) compared to patients randomized to placebo who received a median of 8 infusions (range 2 to 32). To control for disparate exposure between arms, Table 3 reports the per patient incidence of adverse reactions that occurred during the first 8 infusions. Adverse reactions that occurred >3% in the Sylvant arm are presented.

The most common adverse reactions (> 10% compared to placebo) during treatment with Sylvant in the MCD clinical trial were rash, pruritus, upper respiratory tract infection, increased weight, and hyperuricemia.

Table 3: Per Patient Incidence of Common Adverse Reactions in Study 1 During Initial 8 Infusions
Body System/Adverse Reactions	Sylvant+BSC* n=53		Placebo+BSC n=26
	All Grades	Grades 3–4	All Grades	Grades 3–4
* Best Supportive Care † Anaphylactic reaction
Skin disorders
Rash (rash, rash generalized, rash maculo-papular, rash popular and rash pruritic)	15 (28%)	1 (2%)	3 (12%)	0
Pruritus	15 (28%)	0	2 (8%)	0
Skin hyperpigmentation	2 (4%)	0	0	0
Eczema	2 (4%)	0	0	0
Psoriasis	2 (4%)	0	0	0
Dry skin	2 (4%)	0	0	0
Infections
Lower respiratory tract	4 (8%)	2 (4%)	1 (4%)	1 (4%)
Upper respiratory tract	14 (26%)	1 (2%)	4 (15%)	1 (4%)
Blood and lymphatic system disorders
Thrombocytopenia	5 (9%)	2 (4%)	1 (4%)	1 (4%)
General disorders
Edema (general and localized)	14 (26%)	4 (8%)	7 (27%)	0
Gastrointestinal disorders
Constipation	4 (8%)	0	1 (4%)	0
Metabolism
Hypertriglyceridemia	4 (8%)	0	0	0
Hypercholesterolemia	2 (4%)	0	0	0
Hyperuricemia	6 (11%)	1 (2%)	0	0
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	4 (8%)	0	1 (4%)	0
Renal and urinary disorders
Renal impairment	4 (8%)	0	0	0
Nervous system disorders
Headache	4 (8%)	0	1 (4%)	0
Investigations
Weight increased	10 (19%)	1 (2%)	0	0
Vascular disorders
Hypotension	2 (4%)	1 (2%)†	0	0

Study CNTO328MCD2002 (referred to as Study 2) (NCT01400503) was an open label, long term extension study of patients with MCD treated on prior trials. The median duration of siltuximab treatment was 5.52 years (range: 0.8 to 10.8 years); more than 50% of patients received siltuximab treatment for ≥5 years. The rate of serious or Grade ≥3 adverse events did not increase over time as a function of cumulative exposure.

Other important adverse reactions reported in MCD clinical studies, all of which were very common, were:

Infections and infestations: nasopharyngitis, urinary tract infection

Blood and lymphatic system disorders: neutropenia

Nervous system disorders: dizziness

Vascular disorders: hypertension

Gastrointestinal disorders: nausea, abdominal pain, vomiting, diarrhea, gastroesophageal reflux disease, mouth ulceration

Immunogenicity

Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication and the underlying disease. Therefore, comparison of the incidence of antibodies to Sylvant with the incidence of antibodies to other products may be misleading. The clinical significance of anti-siltuximab antibodies following treatment with Sylvant is not known.

The immunogenicity of siltuximab has been evaluated using antigen-bridging enzyme immunoassay (EIA) and electrochemiluminescence-based immunoassay (ECLIA) methods. A total of 432 patients across the clinical studies were evaluated at multiple time points for anti-therapeutic antibody (ATA) responses to siltuximab after treatment with Sylvant. Following Sylvant dosing, 0/243 (0%) patients tested positive for anti-siltuximab antibodies by EIA and 4/189 (2%) patients tested positive by ECLIA. Further immunogenicity analyses were conducted for all positive samples from the 4 patients with detectable anti-siltuximab antibodies. None of these patients had neutralizing antibodies.

Drug InteractionsCytochrome P450 Substrates

Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli including cytokines such as IL-6. Inhibition of IL-6 signaling in patients treated with Sylvant may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment with Sylvant.

Upon initiation or discontinuation of Sylvant, in patients being treated with CYP450 substrates with a narrow therapeutic index, perform therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) as needed and adjust dose. The effect of Sylvant on CYP450 enzyme activity can persist for several weeks after stopping therapy. Exercise caution when Sylvant is co-administered with CYP3A4 substrate drugs where a decrease in effectiveness would be undesirable (e.g., oral contraceptives, lovastatin, atorvastatin).

USE IN SPECIFIC POPULATIONSPregnancy

Pregnancy Category C

Risk-Summary

There are no adequate or well-controlled studies in pregnant women. In animal reproduction studies, administration of a human antibody to IL-6 to pregnant cynomolgus monkeys caused decreases in globulin levels in pregnant animals and in the offspring. Siltuximab crossed the placenta in monkeys. Infants born to pregnant women treated with Sylvant may be at increased risk of infection, and caution is advised in the administration of live vaccines to these infants. Sylvant should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Advise patients of childbearing potential to avoid pregnancy. Women of childbearing potential should use contraception during and for 3 months after treatment.

Animal Data

In an embryo-fetal development study, siltuximab doses of 9.2 or 46 mg/kg/week were administered intravenously to pregnant monkeys during gestation days (GD) 20 to 118, which includes the period of organogenesis. Fetuses were evaluated on GD 140, approximately 25 days prior to the natural birth. Exposures at the low and high dose after the 25th administration were approximately 3 and 7 times respectively the exposure in humans at the recommended dose of 11 mg/kg. There was no siltuximab-related maternal or fetal toxicity. However, siltuximab crossed the placenta at both doses and when measured on GD 140, fetal serum concentrations of siltuximab were similar to maternal concentrations. In a combined embryofetal and pre- and post-natal development study, cynomolgus monkeys were intravenously administered doses of 10 or 50 mg/kg/week of a human antibody to IL-6 from GD 20 to natural delivery (GD 167). The offspring was evaluated up to 7 months after birth for developmental effects. No maternal or infant toxicity was observed; however, globulin levels were decreased in pregnant animals (GD 34 through lactation day 30) and in the offspring (lactation days 30–120) at both doses.

Nursing Mothers

It is not known whether siltuximab is excreted in human milk or absorbed systemically after ingestion. Because many drugs and immunoglobulins are excreted in human milk, and because of the potential for adverse reactions in nursing infants from Sylvant, 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 efficacy of Sylvant have not been established in pediatric patients.

Geriatric Use

Of the patients treated with Sylvant monotherapy in clinical studies 127 (35%) were 65 years and older. No overall differences in safety profile were observed between these patients and younger patients, and other reported clinical experience has not identified differences in the safety profile between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Clinical studies did not include sufficient numbers of patients aged 65 years and older to determine the effect of age on efficacy in MCD population.

Patients with Renal Impairment

Based on a population pharmacokinetic analysis using data from clinical trials in patients, no significant difference in siltuximab clearance was observed in patients with pre-existing renal impairment (creatinine clearance (CLCr) ≥ 15 mL/min) compared to patients with baseline normal renal function (CLCr ≥ 90 mL/min). No initial dosage adjustment is necessary for patients with CLCr ≥ 15 mL/min. The potential effect of end stage renal disease on siltuximab pharmacokinetics cannot be determined [see Clinical Pharmacology (12.3)].

Patients with Hepatic Impairment

Based on a population pharmacokinetic analysis using data from clinical trials in patients, no significant difference in siltuximab clearance was observed in patients with pre-existing mild to moderate hepatic impairment (Child-Pugh Class A and B, respectively) compared to patients with baseline normal hepatic function. No initial dosage adjustment is necessary for patients with mild to moderate hepatic impairment. Patients with baseline severe hepatic impairment (Child-Pugh Class C) were not included in clinical trials [see Clinical Pharmacology (12.3)].

Sylvant Description

Siltuximab is a human-mouse chimeric monoclonal antibody that binds human interleukin-6 (IL-6) and is produced by Chinese hamster ovary cells.

Sylvant (siltuximab) for injection is supplied as a sterile, white, preservative free, lyophilized powder in single-dose vials.

Each Sylvant 100 mg single-dose vial contains 100 mg siltuximab, 3.7 mg L-histidine (from L-histidine and L-histidine monohydrochloride monohydrate), 0.8 mg polysorbate 80, and 169 mg sucrose.

Each Sylvant 400 mg single-dose vial contains 400 mg siltuximab, 14.9 mg L-histidine (from L-histidine and L-histidine monohydrochloride monohydrate), 3.2 mg polysorbate 80, and 677 mg sucrose.

Following reconstitution with Sterile Water for Injection, USP (per section 2.2), the resulting pH is approximately 5.2. The resulting solution contains 20 mg/mL siltuximab to be administered by intravenous infusion following dilution [see Dosage and Administration (2.2)].

Sylvant - Clinical PharmacologyMechanism of Action

Siltuximab binds human IL-6 and prevents the binding of IL-6 to both soluble and membrane-bound IL-6 receptors. IL-6 has been shown to be involved in diverse normal physiologic processes such as induction of immunoglobulin secretion. Overproduction of IL-6 has been linked to systemic manifestations in patients with MCD.

Pharmacodynamics

Cardiac Electrophysiology: The effect of multiple doses of Sylvant (15 mg/kg every 3 weeks for 4 cycles) on the QTc interval was evaluated in an open label, single arm study in 30 patients with Monoclonal Gammopathy of Undetermined Significance, Smoldering Multiple Myeloma, or Indolent Multiple Myeloma. No large changes in the mean QTc interval (i.e., > 20 ms) were detected in the study.

Measurement of IL-6 concentrations in serum or plasma during treatment should not be used as pharmacodynamic marker, as siltuximab-neutralized antibody-IL-6 complexes interfere with current immunological-based IL-6 quantification methods.

Pharmacokinetics

The pharmacokinetics of siltuximab were evaluated in patients with multicentric Castleman's disease and hematological and non-hematological malignancies. The serum siltuximab pharmacokinetics are adequately described by a linear two-compartment intravenous model with first-order elimination.

Distribution

Following Sylvant administration (11 mg/kg, once every 3 weeks as 1-hour intravenous infusion) in patients with multicentric Castleman's disease, the maximum serum siltuximab concentration (Cmax) occurred close to the end of infusion. At steady state, the serum mean Cmax value for siltuximab is 332 mcg/mL (42% CV), and the serum mean predose trough value is 84 mcg/mL (78% CV).

With the once every 3 week dosing regimen, siltuximab steady state is achieved by the sixth infusion, and siltuximab accumulates approximately 1.7-fold relative to a single dose. Following multiple dosing, siltuximab showed approximately dose proportional pharmacokinetics over the dose range of 2.8 to 11 mg/kg.

Based on population pharmacokinetic analysis, the central volume of distribution in a male subject with body weight of 70 kg is 4.5 L (20% CV).

Elimination

Based on the population pharmacokinetic analysis, the clearance of siltuximab in patients is 0.23 L/day (51% CV). Based on population pharmacokinetic analysis (n=378), body weight was identified as the only statistically significant covariate for siltuximab clearance. Therefore, the body weight based dosing is appropriate.

The mean terminal half-life (t1/2) for siltuximab in patients after the first intravenous infusion of 11 mg/kg is 20.6 days (range: 14.2 to 29.7 days).

Specific Populations

Age and Gender

Based on population pharmacokinetic analysis, age [range: 18 to 85 years (n=378)] and gender [female (n=175), male (n=203)] do not affect exposure of siltuximab.

Renal Impairment

A population pharmacokinetic analysis (based on pre-existing renal function) was carried out with data from 377 patients enrolled in clinical trials, including 176 with normal renal function (CLCr ≥ 90 mL/min), 122 with mild renal impairment (CLCr 60 to <90 mL/min), 75 with moderate renal impairment (CLCr 30 to <60 mL/min), and 3 with severe renal impairment (CLCr 15 to 29 mL/min). The apparent clearance of siltuximab was similar in patients with pre-existing mild, moderate and severe renal impairment (CLCr 15 to <90 mL/min) compared to patients with normal renal function. The potential effect of end stage renal disease on siltuximab pharmacokinetics cannot be determined as clinical and pharmacokinetic data are available from only one patient.

Hepatic Impairment

A population pharmacokinetic analysis (based on pre-existing hepatic function) was carried out with data from 377 patients enrolled in clinical trials, including 302 with normal hepatic function, 72 with mild hepatic impairment (Child-Pugh A), and 3 with moderate hepatic impairment (Child-Pugh B). The apparent clearance of siltuximab was similar in patients with pre-existing mild and moderate hepatic impairment (Child-Pugh Class A and B) compared to patients with normal hepatic function. The potential effect of severe hepatic impairment on siltuximab pharmacokinetics cannot be determined as clinical and pharmacokinetic data are not available.

Nonclinical ToxicologyCarcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity or genotoxicity studies have been conducted with siltuximab.

Two fertility studies were conducted. In one study, drug-treated male mice were mated with untreated females and in the second study drug-treated female mice were mated with untreated males. A murine analog of siltuximab was administered subcutaneously at doses up to 100 mg/kg/week for a total of 7 doses in both studies. There was no effect on male or female fertility parameters. In addition, siltuximab did not produce any toxicity in the reproductive organs in cynomolgus monkeys in the 6-month repeat-dose toxicology study at doses up to 46 mg/kg (approximately 7 times) the systemic exposure in patients at the recommended dose.

Clinical Studies

Study 1

Study CNTO328MCD2001 (referred to as Study 1) (NCT01024036) was a Phase 2, multinational, randomized (2:1) double blind, placebo controlled study to evaluate the clinical efficacy and safety of Sylvant for the treatment of patients with MCD. In this study 53 patients were randomized to Best Supportive Care (BSC) and Sylvant at a dose of 11 mg/kg every 3 weeks and 26 patients were randomized to BSC and placebo. The median age was 48 years (range 20 to 78), 66% male, 48% Asian, 39% White, 4% Black or African American, 7% other. The histological subtype of MCD was similar in both treatment arms, with 33% hyaline vascular subtype, 23% plasmacytic subtype and 44% mixed subtype. Treatment was continued until treatment failure (defined as disease progression based on increase in symptoms, radiologic progression or deterioration in performance status) or unacceptable toxicity.

The major efficacy outcome of the study was durable tumor and symptomatic response, defined as tumor response (PR and CR based on modified International Working Group response criteria for malignant lymphoma) assessed by independent review and complete resolution or stabilization of MCD symptoms. Thirty-four MCD related signs and symptoms prospectively identified were collected and graded according to the NCI-CTCAE v 4, by investigators. A durable response was defined as tumor and symptomatic response that persisted for a minimum of 18 weeks without treatment failure. The durable tumor and symptomatic response in the Sylvant arm was 34% compared to 0% in the placebo arm (95% CI: 11.1, 54.8; p=0.0012).

Other analyses included tumor response, time to treatment failure and an increase in hemoglobin of 1.5 g/dL or more, in patients who were anemic at time of study entry, at week 13. The results are summarized in Table 4.

Table 4: Efficacy Endpoints From Study 1
Efficacy Endpoint	Sylvant n=53	Placebo n=26	p-value*
* Adjusted for corticosteroid use at randomization † NR="Not Reached"
Durable tumor and symptomatic response (independent review)	34%	0	0.0012
Tumor response	38%	4%	<0.05
Median time to treatment failure (days)	NR†	134	<0.05
≥1.5 g/dL increase in hemoglobin	61% (19/31)	0% (0/11)	<0.05

A consistent treatment effect was confirmed on subgroup analysis for all parameters evaluated with the exception of the hyaline vascular histological subtype. There were no patients with hyaline vascular histology who demonstrated a durable tumor and symptomatic response. However, activity was suggested in this subtype based on change in hemoglobin and median time to treatment failure.

At the time of the analysis, overall survival data were not mature. One year survival rate was 100% in the Sylvant arm and 92% in the placebo arm.

How Supplied/Storage and HandlingHow Supplied

Sylvant (siltuximab) for injection is supplied as a sterile, white, preservative free, lyophilized powder in single-dose vials.

Each Sylvant vial is individually packaged in a carton:

· NDC 57894-420-01 contains one 100 mg vial

· NDC 57894-421-01 contains one 400 mg vial

Storage and Stability

Sylvant must be refrigerated at 2ºC to 8ºC (36ºF to 46ºF) in the original carton to protect from light. Do not freeze. Do not use Sylvant beyond the expiration date (EXP) located on the carton and the vial.

Patient Counseling Information

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

Instruct the patient of the risks of Sylvant treatment.

Infections

Inform patients that Sylvant may lower their resistance to infections. Instruct the patient of the importance of contacting their doctor immediately when symptoms suggesting infection appear in order to assure rapid evaluation and appropriate treatment.

Vaccination

Inform the patient that they should discuss the recommended vaccinations prior to treatment with Sylvant.

Allergic Reactions

Advise patients to seek immediate medical attention if they experience any symptoms of serious allergic reactions during the infusion. Signs include: difficulty breathing, chest tightness, wheezing, severe dizziness or light-headedness, swelling of the lips or skin rash.

Pregnancy

Advise patients of childbearing potential to avoid pregnancy which may include use of contraception during treatment and for 3 months after Sylvant therapy.

Other Medical Conditions

Advise patients to report any signs of new or worsening medical conditions.

Manufactured by:
Janssen Biotech, Inc., Horsham, PA 19044
U.S. License No. 1864

At: Cilag AG, Schaffhausen, Switzerland

Product of the Netherlands

© Janssen Biotech, Inc. 2015

This Patient Information has been approved by the U.S. Food and Drug Administration.		Revised: 05/2018
PATIENT INFORMATION Sylvant® (Sil-vant) (siltuximab) for injection
What is Sylvant? Sylvant is a prescription medicine used to treat people with multicentric Castleman's disease (MCD) who do not have human immunodeficiency virus (HIV) and human herpesvirus-8 (HHV-8) infection. It is not known if Sylvant is safe and effective in children.
Who should not receive Sylvant? Do not receive Sylvant if you have had a severe allergic reaction to siltuximab or any of the ingredients in Sylvant. See the end of this leaflet for a complete list of ingredients in Sylvant.
Before you receive Sylvant, tell your healthcare provider about all of your medical conditions, including if you: · have an infection. You should not receive Sylvant if you have a severe infection. · have had a recent vaccination or are scheduled to receive any vaccinations. You should not receive a live vaccine during your treatment with Sylvant. · have or have had any stomach or bowel (intestine) problems, such as diverticulitis or ulcers. Tell your healthcare provider if you have pain in your stomach area. · are pregnant or plan to become pregnant. It is not known if Sylvant will harm your unborn baby. You should not become pregnant while receiving treatment with Sylvant. Females who are able to become pregnant should use effective birth control during treatment with Sylvant and for 3 months after stopping treatment. · are breastfeeding or plan to breastfeed. It is not known if Sylvant passes into your breast milk. You and your healthcare provider should decide if you will take Sylvant 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.
How will I receive Sylvant? · Sylvant is given by an intravenous (IV) infusion into a vein over 1 hour. · Sylvant is given every 3 weeks.
What are the possible side effects of Sylvant? Sylvant may cause serious side effects, including: · Infections. Sylvant may lower your ability to fight infections. Tell your healthcare provider right away if you have any signs or symptoms of an infection during treatment with Sylvant. · Infusion and allergic reactions. If you have an infusion or allergic reaction while receiving Sylvant, your healthcare provider will stop your infusion and treat your reaction. If you have a severe infusion or allergic reaction, your healthcare provider may stop your treatment completely. Tell your healthcare provider or get medical help right away if you have any of these symptoms during or after your infusion of Sylvant:
	back pain chest pain or tightness nausea and vomiting flushing redness irregular heart beat (palpitations)	trouble breathing wheezing dizziness or light-headedness swelling of the lips skin rash headache itching
The most common side effects of Sylvant include: rash, itching, upper respiratory tract infection, swelling, weight gain, and increased blood level of uric acid. These are not all the possible side effects of Sylvant. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
General information about the safe and effective use of Sylvant Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your healthcare provider or pharmacist for information about Sylvant that is written for health professionals.
What are the ingredients in Sylvant? Active ingredient: siltuximab Inactive ingredients: L-histidine and L-histidine monohydrochloride monohydrate, polysorbate 80, and sucrose Manufactured by: Janssen Biotech, Inc., Horsham, PA 19044 U.S. License No. 1864 At: Cilag AG, Schaffhausen, Switzerland Product of the Netherlands For more information, call 1-800-526-7736 or go to www.Sylvant.com.

PRINCIPAL DISPLAY PANEL - 100 mg Vial Carton

NDC 57894-420-01

Single Use Only
Discard Unused Portion

Sylvant®
(siltuximab)

For Injection

100 mg

For Intravenous
Infusion Only

Reconstitution: Reconstitute with
5.2 mL Sterile Water for Injection, USP.
Dilution: Must be further diluted with
5% Dextrose Injection, USP.

Janssen Biotech, Inc.
Rx Only

PRINCIPAL DISPLAY PANEL - 400 mg Vial Carton

NDC 57894-421-01

Single Use Only
Discard Unused Portion

Sylvant®
(siltuximab)

For Injection

400 mg

For Intravenous Infusion Only

Reconstitution: Reconstitute with
20 mL Sterile Water for
Injection, USP.
Dilution: Must be further diluted with
5% Dextrose Injection, USP.

Janssen Biotech, Inc.
Rx Only

Sylvant siltuximab injection, powder, lyophilized, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:57894-420 Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength siltuximab (siltuximab) siltuximab 100 mg

Inactive Ingredients Ingredient Name Strength histidine   histidine monohydrochloride monohydrate   polysorbate 80   sucrose

Packaging # Item Code Package Description   1 NDC:57894-420-01 1 VIAL, SINGLE-USE in 1 CARTON   1   1 INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION in 1 VIAL, SINGLE-USE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA125496 04/23/2014

Sylvant siltuximab injection, powder, lyophilized, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:57894-421 Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength siltuximab (siltuximab) siltuximab 400 mg

Inactive Ingredients Ingredient Name Strength histidine   histidine monohydrochloride monohydrate   polysorbate 80   sucrose

Packaging # Item Code Package Description   1 NDC:57894-421-01 1 VIAL, SINGLE-USE in 1 CARTON   1   1 INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION in 1 VIAL, SINGLE-USE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA125496 04/01/2014

Labeler - Janssen Biotech, Inc. (099091753)

Registrant - Janssen Pharmaceuticals, Inc. (063137772)

Establishment
Name	Address	ID/FEI	Operations
Janssen Biologics BV		409612918	API MANUFACTURE(57894-420, 57894-421)
Establishment
Name	Address	ID/FEI	Operations
Janssen Sciences Ireland UC		986030167	API MANUFACTURE(57894-420, 57894-421)

Establishment
Name	Address	ID/FEI	Operations
Cilag AG		483237103	MANUFACTURE(57894-420, 57894-421)

 

Janssen Biotech, Inc.