通用中文 | 赛培立贝注射剂 | 通用外文 | sebelipase αlfa |
品牌中文 | 品牌外文 | Kanuma | |
其他名称 | |||
公司 | Alexion(Alexion) | 产地 | 美国(USA) |
含量 | 2mg/ml | 包装 | 20mg/10ml瓶/盒 |
剂型给药 | 储存 | 室温 | |
适用范围 | 溶酶体酸性脂肪酶缺乏 |
通用中文 | 赛培立贝注射剂 |
通用外文 | sebelipase αlfa |
品牌中文 | |
品牌外文 | Kanuma |
其他名称 | |
公司 | Alexion(Alexion) |
产地 | 美国(USA) |
含量 | 2mg/ml |
包装 | 20mg/10ml瓶/盒 |
剂型给药 | |
储存 | 室温 |
适用范围 | 溶酶体酸性脂肪酶缺乏 |
Kanuma(sebelipase α)使用说明书2015年第一版
标签: sebelipase-α 溶酶体酸性脂肪酶缺乏 商品名kanuma 突破性治疗指定优先审 孤儿药物 |
分类: 药物使用说明书 |
Kanuma(sebelipase-α)使用说明书2015年第一版
批准日期:2015年12月8日;公司:Alexion Pharmaceuticals,Inc.
FDA批准在儿童和成年患者治疗一种罕见酶疾病的第一个药物
药物评价和研究中心主任说:“LAL缺乏是一种罕见遗传的基因疾病可能导致严重和威胁生命器官损伤,尤其是在婴儿开始发病时” “使用这种技术,这些患者 首次获得一种治疗的机会可能改善他们的生命和生存的机会。”兽药中心CVM主任Bernadette Dunham,D.V.M.,Ph.D.说:“我们审评数据的全部确保母鸡在它们的蛋清中没有产生rhLAL,没有遭受来自引入rDNA 构建的任何不良健康影响。公司已采取严格步骤确保邻近鸡没有鸡蛋也没有进入食品供应,和我们通过检查制造设备已验证他们的围堵系统。” 孤儿药物,突破性治疗,优先审评和罕见儿童疾病优先审评凭证
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125561s000lbl.pdf
处方资料重点
这些重点不包括安全和有效使用KANUMA所需所有资料。请参阅KANUMA完整处方资料。
KANUMA(sebelipase α)注射液,为静脉使用
美国初次批准:2015
适应证和用途
KANUMA™是一种特异性水解溶酶体胆固醇酯和甘油三酯酶适用为有溶酶体酸性脂肪酶(LAL)缺乏诊断患者的治疗。(1)
剂量和给药方法
患者生命前6个月中呈现迅速地进展LAL缺乏:推荐的起始剂量为1 mg/kg作为一个静脉输注每周1次。对没有实现最佳临床反应患者,增加至3 mg/kg每周1次。(2.1)
有LAL缺乏儿童和成年患者:推荐剂量为1 mg/kg作为一个静脉输注每隔周1次。(2.1)
给药指导(2.3):
⑴ 至少历时2小时输注。
⑵对3 mg/kg剂量或如发生一个超敏性反应考虑进一步延长输注时间。
⑶对1 mg/kg剂量耐受输注患者考虑1-小时输注。
剂型和规格
注射液:20 mg/10 mL(2 mg/mL)溶液在一次性小瓶中。(3)
禁忌证
无。(4)
警告和注意事项
超敏性反应包括过敏反应:输注期间和后观察患者。根据反应的严重程度考虑中断输注或降低输注速率。如发生一个严重超敏性反应,立即停止输注和开始适当的治疗。用解热药和/或抗组织胺类预先治疗在那些需要对症治疗的病例中可能预防随后的反应。(5.1)
对蛋或蛋产品超敏性:在有已知全身性超敏性反应对蛋或蛋产品患者考虑治疗的风险和获益。(5.2)
不良反应
最常见不良反应是:
生命前6个月中呈现有迅速地进展疾病患者(≥30%):腹泻,呕吐,发热,鼻炎,贫血,咳嗽,鼻咽炎,和荨麻疹。(6.1)
儿童和成年患者(≥8%):头痛,发热,口咽部疼痛,鼻咽炎,乏力,便秘,和恶心。(6.1)
报告怀疑不良反应,联系Alexion电话1-844-259-6783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
KANUMA™ 是适用为有溶酶体酸性脂肪酶(LAL)缺乏诊断患者的治疗。
2 剂量和给药方法
2.1 剂量
生命前6个月中呈现迅速地进展性LAL缺乏患者:
推荐的起始剂量是作为一个静脉输注1 mg/kg给予每周1次。对未实现一个最佳临床反应患者,增加至3 mg/kg每周1次。
有LAL缺乏儿童和成年患者:
推荐剂量是作为一个静脉输注1 mg/kg给予每隔周1次。
2.2 制备指导
KANUMA是只为静脉输注。用以下步骤制备KANUMA。
1.根据患者的体重确定所需小瓶数和推荐剂量1 mg/kg或3 mg/kg,用以下计算(a-b):
a. 总剂量(mg) = 患者体重(kg) × 推荐剂量(mg/kg)
b. 小瓶的总数 = 总剂量(mg)除以20 mg/小瓶
2. 取整至下一个完整小瓶和从冰箱取出所需小瓶数让它们达到室温。
a.计算的总剂量的体积(mL) = 总剂量(mg)除以2 mg/mL浓度
b.为稀释0.9%氯化钠的体积(mL) =患者体重(见表1)的总输注体积(mL) – 计算总剂量体积(mL)
1. 通过倒置轻轻混合。不要摇动小瓶或已制备的输注液。
2. 给药前应视力观察溶液颗粒物质和变色。溶液应是清澈至略微乳白色,无色至略微有色溶液。在小瓶或稀释溶液中可能存在薄,半透明颗粒或纤维。如溶液呈云雾状或如观察到颗粒物质不要使用。
3. 小瓶只为一次性使用。遗弃任何未使用产品。不要冻结。
2.3 给药指导
作为一个静脉输注用一个低蛋白结合输注组件与一个在线,低-蛋白结合0.2微米滤膜给予稀释溶液。
至少历时2小时输注。对接受3 mg/kg剂量或曽经受超敏性反应患者考虑进一步延长输注时间[见警告和注意事项(5.1)]。对接受1 mg/kg剂量耐受输注患者可能考虑1-小时输注。
2.4 已稀释溶液的贮存
KANUMA不含防腐剂;因此,产品应稀释后立即被使用。如不可能立即使用,已稀释超差品在冰箱在2°C至8°C(36°F至46°F)可能被贮存至24小时。不要冻结或摇晃。避光保护。
3 剂型和规格
注射液:20 mg/10 mL(2 mg/mL)溶液在一次性小瓶中.
4 禁忌证
无。
5 警告和注意事项
5.1 超敏性反应包括过敏反应
在KANUMA-治疗患者曽报道超敏性反应,包括过敏反应。在临床试验中,3/106(3%)用Kanuma治疗患者经受体征和症状与过敏反应一致。这些患者输注期间经受反应有体征和症状包括胸部不适,结膜充血,呼吸困难,全身和痒皮疹,充血,眼睑肿胀,流鼻涕,严重呼吸窘迫,心动过速,呼吸急促,和荨麻疹。过敏反应曽发生早在第6次输注和晚至治疗开始后1年。
在临床试验中,21/106(20%)KANUMA-治疗患者,包括9/14(64%)婴儿和12/92(13%)儿童患者,4岁和以上,和成年,经受体征和症状或一致或可能是与一个超敏性反应相关。超敏性反应体征和症状,发生在两或更多患者,包括腹痛,激动,发热,畏寒,腹泻,湿疹,水肿,高血压,易怒,喉水肿,恶心,苍白,瘙痒,皮疹,和呕吐。反应的多数发生在输注期间或输注完成4小时内。在这些临床试验KANUMA输注前患者在输注前没有常规预先给药。
由于对过敏反应潜能,当KANUMA被给予时应容易可得到适当药物支持。如发生过敏反应,立即终止输注和开始适当的药物治疗。输注期间和后严密观察患者。告知患者过敏反应的体征和症状,和指导他们发生体征和症状应立即寻求医疗护理。
超敏性反应的处理应根据反应的严重程度和可能包括暂时中断输注,降低输注速率,和/或用抗组织胺类,解热药,和/或皮质激素治疗。如中断,输注可能在较低速率恢复与当耐受增加。 用解热药和/或抗组织胺类预先治疗在那些病例其中需要对症治疗可能预防随后反应。如发生一个严重超敏性反应,立即终止输注和开始适当的药物治疗。
一个严重反应后再-给予KANUMA考虑风险和获益。监视患者,用可得到的适当复苏措施,做决定是否再给予产品。
5.2 对蛋或蛋产品超敏性
KANUMA被基因工程鸡的蛋清中生产。有已知蛋过敏史患者被排除临床试验以外。在有已知对蛋或蛋产品全身超敏性反应患者中用KANUMA考虑治疗的风险和获益,
6 不良反应
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。
在临床试验中,总共106例患者接受用KANUMA治疗。下面描述数据反映在临床试验中对KANUMA在75例接受KANUMA在剂量至3 mg/kg每周1次患者暴露:
● 9例患者(5例男性,4例女性)曽有生长障碍或生命前6个月中呈现迅速地进展LAL缺乏其他证据接受KANUMA共至165周(中位数60周)在递增剂量范围0.35 mg/kg和5 mg/kg间每周1次[见临床研究(14.1)]。对这些患者推荐初始剂量是1 mg/kg递增至3 mg/kg每周1次[见剂量和给药方法(2.1)]。
● 66例有LAL缺乏儿童和成年患者年龄4至58岁(33例男性,33例女性)接受KANUMA 1 mg/kg 每隔周直至36周。
表2总结在有生命前6个月中呈现迅速地进展LAL缺乏患者接受KANUMA中>30%发生最常见不良反应。
在有生命前6个月中呈现迅速地进展疾病患者接受 KANUMA报道的其他较低常见不良反应 包括肌张力低下,血氧饱和度减低,干呕,喷嚏,和心动过速。
表3总结有LAL缺乏儿童和成年患者接受 KANUMA在一个剂量1 mg/kg每隔周1次在20-周双盲治疗阶段时发生≥8%最常见不良反应[见临床研究(14.2)]。
在儿童和成年患者接受KANUMA报道的其他较低常见其他不良反应包括焦虑和胸部不适。
高脂血症
在KANUMA开始后2和4周分别观察到29/36(81%)和21/36(58%)患者循环LDL-胆固醇(LDL-c)和甘油三酯增高超过治疗前值[见临床药理学(12.2)]。对LDL-c在2周最大增加均数百分率是18%和对甘油三酯在周4是5%。
6.2 免疫原性
如同所有治疗性蛋白,存在对免疫原性潜能。患者曾发生对KANUMA抗-药物抗体(ADA)。免疫原性分析结果是高度依赖于分析的灵敏度和特异性和可能受几种因素影响例如:分析方法学,样品处理,采样时间,同时药物,和所患疾病。因为这些理由,比较对KANUMA抗体的发生率与对其他产品抗体的发生率可能是误导。
生命前6个月中呈现有迅速地进展LAL缺乏患者
有迅速地进展疾病婴儿7/9例至少有一次治疗后ADA评估,而这些4/7(57%)患者用KANUMA治疗期间发生ADA。2/4的ADA-阳性患者被确定是对中和抗体阳性,在体外抑制酶活性和酶的细胞摄入。在初始ADA阳性的时间,3例患者被接受一个剂量1 mg/kg每周1次和1例患者被接受一个剂量3 mg/kg每周1次。3/4例ADA-阳性患者从治疗的开始有监测的ADA滴度,和从暴露的头2个月内发生可测量的ADA滴度。1/4例ADA-阳性患者有持久的ADA滴度。剩余3例患者同时继续接受治疗在剂量3 mg/kg每周1次ADA滴度减低至不能检测到水平。
在所有4例ADA-阳性患者发生超敏性反应,而ADA-阴性患者只1/3例发生。没有患者终止治疗。观察到在1例患者对KANUMA中和抗体情况中减低生长速率。
有LAL缺乏儿童和成年患者
5/35例(14%)KANUMA-治疗儿童和成年患者完成20-周双盲期研究治疗发生ADA。所有患者正在接受1 mg/kg每隔周1次。所有5例ADA-阳性患者在暴露的头3个月内首次发生可测量的ADA滴度。2/5例ADA-阳性患者只在一个时间点有可测量的ADA滴度。在3例患者在多个时间点有可测量ADA滴度,在继续治疗期间ADA滴度减低至不可测量水平。2例患者在开放延伸期时分别在用KANUMA治疗20周和52周后发生体外中和抗体。用Kanuma治疗儿童和成年患者中发生ADA和减低疗效间无明确关联。
8 在特殊人群中使用
8.1 妊娠
风险总结
在妊娠妇女用KANUMA没有可得到数据已告知任何药物关联风险。用sebelipase α进行动物生殖研究显示在大鼠和兔,在剂量为人剂量1 mg/kg每隔周(根据AUC)分别至164和526倍无胚胎致死性,胎儿毒性,致畸胎性,或异常早期胚胎发育的证据。
不知道在适应证人群主要出生缺陷和流产的背景风险。在美国一般人群中,主要出生缺陷和临床认可妊娠中流产的估算背景风险分别是2至4%和15至20%。
动物数据
在器官形成期时给予大鼠(在怀孕第6,9,12,15和17天) 和兔(在怀孕第7,10,13,16和19天)Sebelipase α在静脉剂量分别至60和50 mg/kg,(在人1 mg/kg剂量给予每隔周1次人AUC 1387 ng.h/mL约分别164和526倍)对胚胎胎儿发育没有致任何不良影响。在大鼠一项围产期发育研究显示在静脉剂量(在怀孕第6,9,12,15,18,和20天和产后第4,7,10,14,和17天给予)sebelipase α至60 mg/kg/day(约人在1 mg/kg剂量给予每隔周1次人AUC 1387 ng.h/mL的164倍)对围产期发育没有不良影响的证据。
8.2 哺乳
风险总结
对人乳汁中sebelipase α的存在,对哺乳喂养婴儿影响,or the effects 对乳汁产生的影响没有数据。不知道sebelipase α是否在动物乳汁中存在。哺乳喂养的发育和健康获益应与母亲对KANUMA临床需求和哺乳喂养婴儿来自sebelipase α或来自母体所患情况任何潜在不良影响一并考虑。
8.4 儿童使用
尚未在儿童患者年龄1个月和以上确定KANUMA的安全性和有效性。在56例儿童患者(范围1个月至<18岁)用KANUMA进行临床试验[见临床研究(14)]。
8.5 老年人使用
KANUMA的临床试验没有包括任何年龄65岁和以上患者。不知道他们的反应与较年轻患者是否不同。
11 一般描述
KANUMA(sebelipase α)是一种重组人溶酶体酸性脂肪酶(rhLAL)。溶酶体酸性脂肪酶(EC 3.1.1.13)是一种溶酶体糖蛋白酶that 催化胆甾醇酯的水解至释放胆固醇和脂肪酸和水解甘油
通过重组DNA技术通过遗传工程化鸡产的卵在蛋的蛋清中生产KANUMA。纯制的sebelipase α 是一个单体糖蛋白含6个N-连接糖基化位点和有一个分子质量接近55,000道尔顿。对sebelipase α的氨基酸序列是与人LAL氨基酸序列相同。Sebelipase α的比活性是195至345单位/mg。酶活性量的一个单位在指定分析条件下在37°C每分钟催化1个微克分子的合成底物4-甲基伞形酮油酸酯[methylumbelliferyl oleate]的水解。
KANUMA以一种无菌,无防腐剂,无热原水性溶液在一次性小瓶中为静脉输注供应。每小瓶含sebelipase α 20 mg/10 mL,每mL溶液含sebelipase α(2 mg),柠檬酸一水合物(1.57 mg),人血清白蛋白(10 mg),和柠檬酸三钠二水合物(13.7 mg)在pH 5.9。
12 临床药理学
12.1 作用机制
LAL缺乏是一种常染色体隐性溶酶体贮积疾病特征是遗传缺陷导致溶酶体酸性脂肪酶(LAL)酶活性的明显减低或丧失。LAL酶的主要作用部位是溶酶体,在那里酶正常地致脂质颗粒包括循环LDL-胆固醇[LDL-c]分解。LAL酶活性的缺乏导致由于在多个器官,包括肝,脾,小肠,和血管壁溶酶体中胆固醇酯和甘油三酯积蓄进行性并发症。脂质在肝中蓄积的结果导致肝脂肪含量增加和肝病进展,包括纤维化和硬化,在小肠壁脂质蓄积导致吸收不良和生长衰竭。平行地,血脂异常 由于溶酶体脂质降解的受损常与升高的LDL-c和甘油三酯和低HDL-胆固醇(HDL-c)。
Sebelipase α通过蛋白上表达的聚糖[glycans]结合至细胞表面受体和随后被内化至溶酶体。 Sebelipase α催化胆固醇酯和甘油三酯的溶酶体水解至游离胆固醇,甘油和游离脂肪酸。
12.2 药效动力学
在临床试验中,用KANUMA给药开始后,治疗的头2至4周内积蓄的溶酶体脂质降解导致循环LDL-胆固醇[LDL-c]和甘油三酯初始增加。一般,在LDL-c和甘油三酯增加后,用KANUMA治疗8周内这些参数减低至低于治疗前值。
在所有在基线时有升高的谷丙转氨酶(ALT)患者(在临床试验中82/84患者),一般地KANUMA治疗开始后2周内观察到ALT值减低。治疗中断导致LDL-c和ALT值增加和HDL-c减低。
12.3 药代动力学
Sebelipase α的药代动力学图形是非线性有1和3 mg/kg间暴露中增加大于剂量正比例根据非-房室分析来自26例成年数据。每周1次或每隔周1次给药后观察到无积蓄。
利用群体药代动力学模型,对65例儿童和成年患者接受KANUMA静脉输注在1 mg/kg在周22估算sebelipase α 药代动力学参数(表4);24例患者是4 至11岁,23例是12至17岁,和18例是成年。青少年和成年间sebelipase α的药代动力学图形相似。跨越所有年龄组Tmax和T1/2是相似。
13 非临床毒理学
13.1 癌发生,突变发生,生育力受损
未曽用sebelipase α进行动物中评价致癌性潜能长期研究或研究评价致突变性。发现Sebelipase α在静脉剂量至60 mg/kg每周给予2次(在1 mg/kg剂量每隔周1次给予时为人AUC 1387 ng.h/mL约164倍)对雄性和雌性大鼠的生育力和生殖性能无不良影响。
13.2 动物毒理学和/或药理学
在一个大鼠LAL缺乏疾病模型表现与人类疾病类似的几种异常,静脉给予sebelipase α在剂量至3 mg/kg每周1次显示生存,体重增量,器官重减低,血清转氨酶(ALT和谷草转氨酶[AST]),血清和肝脂质减低的改善,和肝脏组织病理学改善。
14 临床研究
14.1 有生命前6个月中呈现迅速地进展LAL缺乏患者
在9例有LAL缺乏6个月龄前有生长障碍或迅速地进展疾病的其他证据婴儿进行一项多中心,开放,单臂KANUMA临床研究。纳入时年龄范围为1至6个月。患者接受KANUMA在0.35 mg/kg 每周1次共头2周和然后1 mg/kg每周1次。由于次优临床反应,在1 mg/kg治疗开始后,在4和88周间(中位数11周),所有6例生存患者剂量被递增至3 mg/kg每周1次。在一例患者中,在周88时由于减低生长速率在中和对KANUMA抗-药抗体阳性情况下剂量被递增至5 mg/kg每周1次。对这些患者推荐剂量是1 mg/kg至3 mg/kg每周1次[见剂量和给药方法(2.1)]。
通过比较9例12月龄KANUMA-治疗患者与21例有在疾病疾病的表现和临床特点相似月龄患者的未治疗历史队列的生存评估KANUMA的疗效。9例KANUMA-治疗婴儿中,6例患者生存超过12月龄,与之比较,在历史队列中为0/21患者,他们所有都在8月龄死亡。6例生存KANUMA-治疗患者中位年龄为18.1个月(范围12至42.2个月)。
用KANUMA 1 mg/kg每周1次治疗开始后,在有生长障碍生存的患者中3/5的体重-对-年龄z-评分改善,和剂量递增至3 mg/kg每周1次后所有6例生存患者显示体重-对-年龄z-评分改善。
14.2 有LAL缺乏儿童和成年患者
在一项多中心,双盲,安慰剂-对照试验在66例有LAL缺乏儿童和成年患者,年龄4至58岁(71%低于18岁)评估KANUMA的安全性和疗效。在双盲期患者被随机化接受KANUMA在一个剂量1 mg/kg(n=36)或安慰剂(n=30)每隔周1次共20周。62/66(94%)患者有循环LDL-胆固醇[LDL-c] 130 mg/dL或大于在研究纳入时。在研究纳入时患者的多数(58%)有LDL-c高于190 mg/dL,和有LDL-c高于190 mg/dL患者24%保持用降脂药物。
在试验20-周双盲期的完成,在KANUMA-治疗组当与安慰剂组比较观察到LDL-c从基线变化百分率统计显著改进(均数差异和95% C.I.:-22%,[-33%,-15%]; p<0.0001)。KANUMA-治疗患者13/32例(41%; 95% C.I.:[24%,58%])实现LDL-c低于130 mg/dL而安慰剂-治疗患者有基线LDL-c 130 mg/dL或以上只有2/30(7%; 95% C.I.:[0%,16%])。A in percent change在20周时还观察到KANUMA-治疗组与安慰剂组比较对与LAL缺乏相关其他参数从基线变化百分率统计学显著改进,包括非-HDL-c中减低(均数差别和95% C.I.:-21%,[-30%,-15%]; p<0.0001)和甘油三酯(均数差别和95% C.I.:-14%,[-28%,-1%]; p=0.0375),和HDL-c增高(均数差别和95% C.I.:20%,[12%,26%]; p<0.0001)。尚未确定KANUMA对心血管发病率和死亡率的影响。
与用安慰剂治疗患者比较,用Kanuma治疗患者有ALT值和肝脂肪含量(用MRI测量)从基线较大减低。尚未确定在LAL缺乏这些发现的意义如它们与肝脏病进展相关。
开放延伸
在一项开放延伸试验,随机化,安慰剂-对照试验参加儿童和成年患者是合格继续治疗。65/66例患者(98%)进入开放期其中所有患者接受KANUMA在一个剂量1 mg/kg每隔周1次。开放延伸期间,用Kanuma治疗患者共至36周证实脂质参数改善,包括LDL-c和HDL-c水平,和ALT。
16 如何供应/贮存和处置
KANUMA 20 mg/10 mL小瓶以无菌,无防腐剂,无热原溶液在一次性,玻璃小瓶供应。
NDC 25682-007-01:20 mg/10 mL小瓶
KANUMA贮存在冰箱2°C至8°C(36°F至46°F)间在原始纸盒中避光保护。不要摇晃或冻结小瓶。
17 患者咨询资料
超敏性反应,包括过敏反应
忠告患者和护理人员在KANUMA治疗期间和后可能发生与给药和输注相关反应,包括威胁生命过敏反应和严重超敏性反应。告知患者过敏反应和超敏性反应的体征和症状,和发生体征和症状应立即寻求医疗护理[见警告和注意事项(5.1)
Kanuma(sebelipase α)使用说明书2015年第一版
标签: sebelipase-α 溶酶体酸性脂肪酶缺乏 商品名kanuma 突破性治疗指定优先审 孤儿药物 |
分类: 药物使用说明书 |
Kanuma(sebelipase-α)使用说明书2015年第一版
批准日期:2015年12月8日;公司:Alexion Pharmaceuticals,Inc.
FDA批准在儿童和成年患者治疗一种罕见酶疾病的第一个药物
药物评价和研究中心主任说:“LAL缺乏是一种罕见遗传的基因疾病可能导致严重和威胁生命器官损伤,尤其是在婴儿开始发病时” “使用这种技术,这些患者 首次获得一种治疗的机会可能改善他们的生命和生存的机会。”兽药中心CVM主任Bernadette Dunham,D.V.M.,Ph.D.说:“我们审评数据的全部确保母鸡在它们的蛋清中没有产生rhLAL,没有遭受来自引入rDNA 构建的任何不良健康影响。公司已采取严格步骤确保邻近鸡没有鸡蛋也没有进入食品供应,和我们通过检查制造设备已验证他们的围堵系统。” 孤儿药物,突破性治疗,优先审评和罕见儿童疾病优先审评凭证
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125561s000lbl.pdf
处方资料重点
这些重点不包括安全和有效使用KANUMA所需所有资料。请参阅KANUMA完整处方资料。
KANUMA(sebelipase α)注射液,为静脉使用
美国初次批准:2015
适应证和用途
KANUMA™是一种特异性水解溶酶体胆固醇酯和甘油三酯酶适用为有溶酶体酸性脂肪酶(LAL)缺乏诊断患者的治疗。(1)
剂量和给药方法
患者生命前6个月中呈现迅速地进展LAL缺乏:推荐的起始剂量为1 mg/kg作为一个静脉输注每周1次。对没有实现最佳临床反应患者,增加至3 mg/kg每周1次。(2.1)
有LAL缺乏儿童和成年患者:推荐剂量为1 mg/kg作为一个静脉输注每隔周1次。(2.1)
给药指导(2.3):
⑴ 至少历时2小时输注。
⑵对3 mg/kg剂量或如发生一个超敏性反应考虑进一步延长输注时间。
⑶对1 mg/kg剂量耐受输注患者考虑1-小时输注。
剂型和规格
注射液:20 mg/10 mL(2 mg/mL)溶液在一次性小瓶中。(3)
禁忌证
无。(4)
警告和注意事项
超敏性反应包括过敏反应:输注期间和后观察患者。根据反应的严重程度考虑中断输注或降低输注速率。如发生一个严重超敏性反应,立即停止输注和开始适当的治疗。用解热药和/或抗组织胺类预先治疗在那些需要对症治疗的病例中可能预防随后的反应。(5.1)
对蛋或蛋产品超敏性:在有已知全身性超敏性反应对蛋或蛋产品患者考虑治疗的风险和获益。(5.2)
不良反应
最常见不良反应是:
生命前6个月中呈现有迅速地进展疾病患者(≥30%):腹泻,呕吐,发热,鼻炎,贫血,咳嗽,鼻咽炎,和荨麻疹。(6.1)
儿童和成年患者(≥8%):头痛,发热,口咽部疼痛,鼻咽炎,乏力,便秘,和恶心。(6.1)
报告怀疑不良反应,联系Alexion电话1-844-259-6783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
KANUMA™ 是适用为有溶酶体酸性脂肪酶(LAL)缺乏诊断患者的治疗。
2 剂量和给药方法
2.1 剂量
生命前6个月中呈现迅速地进展性LAL缺乏患者:
推荐的起始剂量是作为一个静脉输注1 mg/kg给予每周1次。对未实现一个最佳临床反应患者,增加至3 mg/kg每周1次。
有LAL缺乏儿童和成年患者:
推荐剂量是作为一个静脉输注1 mg/kg给予每隔周1次。
2.2 制备指导
KANUMA是只为静脉输注。用以下步骤制备KANUMA。
1.根据患者的体重确定所需小瓶数和推荐剂量1 mg/kg或3 mg/kg,用以下计算(a-b):
a. 总剂量(mg) = 患者体重(kg) × 推荐剂量(mg/kg)
b. 小瓶的总数 = 总剂量(mg)除以20 mg/小瓶
2. 取整至下一个完整小瓶和从冰箱取出所需小瓶数让它们达到室温。
a.计算的总剂量的体积(mL) = 总剂量(mg)除以2 mg/mL浓度
b.为稀释0.9%氯化钠的体积(mL) =患者体重(见表1)的总输注体积(mL) – 计算总剂量体积(mL)
1. 通过倒置轻轻混合。不要摇动小瓶或已制备的输注液。
2. 给药前应视力观察溶液颗粒物质和变色。溶液应是清澈至略微乳白色,无色至略微有色溶液。在小瓶或稀释溶液中可能存在薄,半透明颗粒或纤维。如溶液呈云雾状或如观察到颗粒物质不要使用。
3. 小瓶只为一次性使用。遗弃任何未使用产品。不要冻结。
2.3 给药指导
作为一个静脉输注用一个低蛋白结合输注组件与一个在线,低-蛋白结合0.2微米滤膜给予稀释溶液。
至少历时2小时输注。对接受3 mg/kg剂量或曽经受超敏性反应患者考虑进一步延长输注时间[见警告和注意事项(5.1)]。对接受1 mg/kg剂量耐受输注患者可能考虑1-小时输注。
2.4 已稀释溶液的贮存
KANUMA不含防腐剂;因此,产品应稀释后立即被使用。如不可能立即使用,已稀释超差品在冰箱在2°C至8°C(36°F至46°F)可能被贮存至24小时。不要冻结或摇晃。避光保护。
3 剂型和规格
注射液:20 mg/10 mL(2 mg/mL)溶液在一次性小瓶中.
4 禁忌证
无。
5 警告和注意事项
5.1 超敏性反应包括过敏反应
在KANUMA-治疗患者曽报道超敏性反应,包括过敏反应。在临床试验中,3/106(3%)用Kanuma治疗患者经受体征和症状与过敏反应一致。这些患者输注期间经受反应有体征和症状包括胸部不适,结膜充血,呼吸困难,全身和痒皮疹,充血,眼睑肿胀,流鼻涕,严重呼吸窘迫,心动过速,呼吸急促,和荨麻疹。过敏反应曽发生早在第6次输注和晚至治疗开始后1年。
在临床试验中,21/106(20%)KANUMA-治疗患者,包括9/14(64%)婴儿和12/92(13%)儿童患者,4岁和以上,和成年,经受体征和症状或一致或可能是与一个超敏性反应相关。超敏性反应体征和症状,发生在两或更多患者,包括腹痛,激动,发热,畏寒,腹泻,湿疹,水肿,高血压,易怒,喉水肿,恶心,苍白,瘙痒,皮疹,和呕吐。反应的多数发生在输注期间或输注完成4小时内。在这些临床试验KANUMA输注前患者在输注前没有常规预先给药。
由于对过敏反应潜能,当KANUMA被给予时应容易可得到适当药物支持。如发生过敏反应,立即终止输注和开始适当的药物治疗。输注期间和后严密观察患者。告知患者过敏反应的体征和症状,和指导他们发生体征和症状应立即寻求医疗护理。
超敏性反应的处理应根据反应的严重程度和可能包括暂时中断输注,降低输注速率,和/或用抗组织胺类,解热药,和/或皮质激素治疗。如中断,输注可能在较低速率恢复与当耐受增加。 用解热药和/或抗组织胺类预先治疗在那些病例其中需要对症治疗可能预防随后反应。如发生一个严重超敏性反应,立即终止输注和开始适当的药物治疗。
一个严重反应后再-给予KANUMA考虑风险和获益。监视患者,用可得到的适当复苏措施,做决定是否再给予产品。
5.2 对蛋或蛋产品超敏性
KANUMA被基因工程鸡的蛋清中生产。有已知蛋过敏史患者被排除临床试验以外。在有已知对蛋或蛋产品全身超敏性反应患者中用KANUMA考虑治疗的风险和获益,
6 不良反应
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。
在临床试验中,总共106例患者接受用KANUMA治疗。下面描述数据反映在临床试验中对KANUMA在75例接受KANUMA在剂量至3 mg/kg每周1次患者暴露:
● 9例患者(5例男性,4例女性)曽有生长障碍或生命前6个月中呈现迅速地进展LAL缺乏其他证据接受KANUMA共至165周(中位数60周)在递增剂量范围0.35 mg/kg和5 mg/kg间每周1次[见临床研究(14.1)]。对这些患者推荐初始剂量是1 mg/kg递增至3 mg/kg每周1次[见剂量和给药方法(2.1)]。
● 66例有LAL缺乏儿童和成年患者年龄4至58岁(33例男性,33例女性)接受KANUMA 1 mg/kg 每隔周直至36周。
表2总结在有生命前6个月中呈现迅速地进展LAL缺乏患者接受KANUMA中>30%发生最常见不良反应。
在有生命前6个月中呈现迅速地进展疾病患者接受 KANUMA报道的其他较低常见不良反应 包括肌张力低下,血氧饱和度减低,干呕,喷嚏,和心动过速。
表3总结有LAL缺乏儿童和成年患者接受 KANUMA在一个剂量1 mg/kg每隔周1次在20-周双盲治疗阶段时发生≥8%最常见不良反应[见临床研究(14.2)]。
在儿童和成年患者接受KANUMA报道的其他较低常见其他不良反应包括焦虑和胸部不适。
高脂血症
在KANUMA开始后2和4周分别观察到29/36(81%)和21/36(58%)患者循环LDL-胆固醇(LDL-c)和甘油三酯增高超过治疗前值[见临床药理学(12.2)]。对LDL-c在2周最大增加均数百分率是18%和对甘油三酯在周4是5%。
6.2 免疫原性
如同所有治疗性蛋白,存在对免疫原性潜能。患者曾发生对KANUMA抗-药物抗体(ADA)。免疫原性分析结果是高度依赖于分析的灵敏度和特异性和可能受几种因素影响例如:分析方法学,样品处理,采样时间,同时药物,和所患疾病。因为这些理由,比较对KANUMA抗体的发生率与对其他产品抗体的发生率可能是误导。
生命前6个月中呈现有迅速地进展LAL缺乏患者
有迅速地进展疾病婴儿7/9例至少有一次治疗后ADA评估,而这些4/7(57%)患者用KANUMA治疗期间发生ADA。2/4的ADA-阳性患者被确定是对中和抗体阳性,在体外抑制酶活性和酶的细胞摄入。在初始ADA阳性的时间,3例患者被接受一个剂量1 mg/kg每周1次和1例患者被接受一个剂量3 mg/kg每周1次。3/4例ADA-阳性患者从治疗的开始有监测的ADA滴度,和从暴露的头2个月内发生可测量的ADA滴度。1/4例ADA-阳性患者有持久的ADA滴度。剩余3例患者同时继续接受治疗在剂量3 mg/kg每周1次ADA滴度减低至不能检测到水平。
在所有4例ADA-阳性患者发生超敏性反应,而ADA-阴性患者只1/3例发生。没有患者终止治疗。观察到在1例患者对KANUMA中和抗体情况中减低生长速率。
有LAL缺乏儿童和成年患者
5/35例(14%)KANUMA-治疗儿童和成年患者完成20-周双盲期研究治疗发生ADA。所有患者正在接受1 mg/kg每隔周1次。所有5例ADA-阳性患者在暴露的头3个月内首次发生可测量的ADA滴度。2/5例ADA-阳性患者只在一个时间点有可测量的ADA滴度。在3例患者在多个时间点有可测量ADA滴度,在继续治疗期间ADA滴度减低至不可测量水平。2例患者在开放延伸期时分别在用KANUMA治疗20周和52周后发生体外中和抗体。用Kanuma治疗儿童和成年患者中发生ADA和减低疗效间无明确关联。
8 在特殊人群中使用
8.1 妊娠
风险总结
在妊娠妇女用KANUMA没有可得到数据已告知任何药物关联风险。用sebelipase α进行动物生殖研究显示在大鼠和兔,在剂量为人剂量1 mg/kg每隔周(根据AUC)分别至164和526倍无胚胎致死性,胎儿毒性,致畸胎性,或异常早期胚胎发育的证据。
不知道在适应证人群主要出生缺陷和流产的背景风险。在美国一般人群中,主要出生缺陷和临床认可妊娠中流产的估算背景风险分别是2至4%和15至20%。
动物数据
在器官形成期时给予大鼠(在怀孕第6,9,12,15和17天) 和兔(在怀孕第7,10,13,16和19天)Sebelipase α在静脉剂量分别至60和50 mg/kg,(在人1 mg/kg剂量给予每隔周1次人AUC 1387 ng.h/mL约分别164和526倍)对胚胎胎儿发育没有致任何不良影响。在大鼠一项围产期发育研究显示在静脉剂量(在怀孕第6,9,12,15,18,和20天和产后第4,7,10,14,和17天给予)sebelipase α至60 mg/kg/day(约人在1 mg/kg剂量给予每隔周1次人AUC 1387 ng.h/mL的164倍)对围产期发育没有不良影响的证据。
8.2 哺乳
风险总结
对人乳汁中sebelipase α的存在,对哺乳喂养婴儿影响,or the effects 对乳汁产生的影响没有数据。不知道sebelipase α是否在动物乳汁中存在。哺乳喂养的发育和健康获益应与母亲对KANUMA临床需求和哺乳喂养婴儿来自sebelipase α或来自母体所患情况任何潜在不良影响一并考虑。
8.4 儿童使用
尚未在儿童患者年龄1个月和以上确定KANUMA的安全性和有效性。在56例儿童患者(范围1个月至<18岁)用KANUMA进行临床试验[见临床研究(14)]。
8.5 老年人使用
KANUMA的临床试验没有包括任何年龄65岁和以上患者。不知道他们的反应与较年轻患者是否不同。
11 一般描述
KANUMA(sebelipase α)是一种重组人溶酶体酸性脂肪酶(rhLAL)。溶酶体酸性脂肪酶(EC 3.1.1.13)是一种溶酶体糖蛋白酶that 催化胆甾醇酯的水解至释放胆固醇和脂肪酸和水解甘油
通过重组DNA技术通过遗传工程化鸡产的卵在蛋的蛋清中生产KANUMA。纯制的sebelipase α 是一个单体糖蛋白含6个N-连接糖基化位点和有一个分子质量接近55,000道尔顿。对sebelipase α的氨基酸序列是与人LAL氨基酸序列相同。Sebelipase α的比活性是195至345单位/mg。酶活性量的一个单位在指定分析条件下在37°C每分钟催化1个微克分子的合成底物4-甲基伞形酮油酸酯[methylumbelliferyl oleate]的水解。
KANUMA以一种无菌,无防腐剂,无热原水性溶液在一次性小瓶中为静脉输注供应。每小瓶含sebelipase α 20 mg/10 mL,每mL溶液含sebelipase α(2 mg),柠檬酸一水合物(1.57 mg),人血清白蛋白(10 mg),和柠檬酸三钠二水合物(13.7 mg)在pH 5.9。
12 临床药理学
12.1 作用机制
LAL缺乏是一种常染色体隐性溶酶体贮积疾病特征是遗传缺陷导致溶酶体酸性脂肪酶(LAL)酶活性的明显减低或丧失。LAL酶的主要作用部位是溶酶体,在那里酶正常地致脂质颗粒包括循环LDL-胆固醇[LDL-c]分解。LAL酶活性的缺乏导致由于在多个器官,包括肝,脾,小肠,和血管壁溶酶体中胆固醇酯和甘油三酯积蓄进行性并发症。脂质在肝中蓄积的结果导致肝脂肪含量增加和肝病进展,包括纤维化和硬化,在小肠壁脂质蓄积导致吸收不良和生长衰竭。平行地,血脂异常 由于溶酶体脂质降解的受损常与升高的LDL-c和甘油三酯和低HDL-胆固醇(HDL-c)。
Sebelipase α通过蛋白上表达的聚糖[glycans]结合至细胞表面受体和随后被内化至溶酶体。 Sebelipase α催化胆固醇酯和甘油三酯的溶酶体水解至游离胆固醇,甘油和游离脂肪酸。
12.2 药效动力学
在临床试验中,用KANUMA给药开始后,治疗的头2至4周内积蓄的溶酶体脂质降解导致循环LDL-胆固醇[LDL-c]和甘油三酯初始增加。一般,在LDL-c和甘油三酯增加后,用KANUMA治疗8周内这些参数减低至低于治疗前值。
在所有在基线时有升高的谷丙转氨酶(ALT)患者(在临床试验中82/84患者),一般地KANUMA治疗开始后2周内观察到ALT值减低。治疗中断导致LDL-c和ALT值增加和HDL-c减低。
12.3 药代动力学
Sebelipase α的药代动力学图形是非线性有1和3 mg/kg间暴露中增加大于剂量正比例根据非-房室分析来自26例成年数据。每周1次或每隔周1次给药后观察到无积蓄。
利用群体药代动力学模型,对65例儿童和成年患者接受KANUMA静脉输注在1 mg/kg在周22估算sebelipase α 药代动力学参数(表4);24例患者是4 至11岁,23例是12至17岁,和18例是成年。青少年和成年间sebelipase α的药代动力学图形相似。跨越所有年龄组Tmax和T1/2是相似。
13 非临床毒理学
13.1 癌发生,突变发生,生育力受损
未曽用sebelipase α进行动物中评价致癌性潜能长期研究或研究评价致突变性。发现Sebelipase α在静脉剂量至60 mg/kg每周给予2次(在1 mg/kg剂量每隔周1次给予时为人AUC 1387 ng.h/mL约164倍)对雄性和雌性大鼠的生育力和生殖性能无不良影响。
13.2 动物毒理学和/或药理学
在一个大鼠LAL缺乏疾病模型表现与人类疾病类似的几种异常,静脉给予sebelipase α在剂量至3 mg/kg每周1次显示生存,体重增量,器官重减低,血清转氨酶(ALT和谷草转氨酶[AST]),血清和肝脂质减低的改善,和肝脏组织病理学改善。
14 临床研究
14.1 有生命前6个月中呈现迅速地进展LAL缺乏患者
在9例有LAL缺乏6个月龄前有生长障碍或迅速地进展疾病的其他证据婴儿进行一项多中心,开放,单臂KANUMA临床研究。纳入时年龄范围为1至6个月。患者接受KANUMA在0.35 mg/kg 每周1次共头2周和然后1 mg/kg每周1次。由于次优临床反应,在1 mg/kg治疗开始后,在4和88周间(中位数11周),所有6例生存患者剂量被递增至3 mg/kg每周1次。在一例患者中,在周88时由于减低生长速率在中和对KANUMA抗-药抗体阳性情况下剂量被递增至5 mg/kg每周1次。对这些患者推荐剂量是1 mg/kg至3 mg/kg每周1次[见剂量和给药方法(2.1)]。
通过比较9例12月龄KANUMA-治疗患者与21例有在疾病疾病的表现和临床特点相似月龄患者的未治疗历史队列的生存评估KANUMA的疗效。9例KANUMA-治疗婴儿中,6例患者生存超过12月龄,与之比较,在历史队列中为0/21患者,他们所有都在8月龄死亡。6例生存KANUMA-治疗患者中位年龄为18.1个月(范围12至42.2个月)。
用KANUMA 1 mg/kg每周1次治疗开始后,在有生长障碍生存的患者中3/5的体重-对-年龄z-评分改善,和剂量递增至3 mg/kg每周1次后所有6例生存患者显示体重-对-年龄z-评分改善。
14.2 有LAL缺乏儿童和成年患者
在一项多中心,双盲,安慰剂-对照试验在66例有LAL缺乏儿童和成年患者,年龄4至58岁(71%低于18岁)评估KANUMA的安全性和疗效。在双盲期患者被随机化接受KANUMA在一个剂量1 mg/kg(n=36)或安慰剂(n=30)每隔周1次共20周。62/66(94%)患者有循环LDL-胆固醇[LDL-c] 130 mg/dL或大于在研究纳入时。在研究纳入时患者的多数(58%)有LDL-c高于190 mg/dL,和有LDL-c高于190 mg/dL患者24%保持用降脂药物。
在试验20-周双盲期的完成,在KANUMA-治疗组当与安慰剂组比较观察到LDL-c从基线变化百分率统计显著改进(均数差异和95% C.I.:-22%,[-33%,-15%]; p<0.0001)。KANUMA-治疗患者13/32例(41%; 95% C.I.:[24%,58%])实现LDL-c低于130 mg/dL而安慰剂-治疗患者有基线LDL-c 130 mg/dL或以上只有2/30(7%; 95% C.I.:[0%,16%])。A in percent change在20周时还观察到KANUMA-治疗组与安慰剂组比较对与LAL缺乏相关其他参数从基线变化百分率统计学显著改进,包括非-HDL-c中减低(均数差别和95% C.I.:-21%,[-30%,-15%]; p<0.0001)和甘油三酯(均数差别和95% C.I.:-14%,[-28%,-1%]; p=0.0375),和HDL-c增高(均数差别和95% C.I.:20%,[12%,26%]; p<0.0001)。尚未确定KANUMA对心血管发病率和死亡率的影响。
与用安慰剂治疗患者比较,用Kanuma治疗患者有ALT值和肝脂肪含量(用MRI测量)从基线较大减低。尚未确定在LAL缺乏这些发现的意义如它们与肝脏病进展相关。
开放延伸
在一项开放延伸试验,随机化,安慰剂-对照试验参加儿童和成年患者是合格继续治疗。65/66例患者(98%)进入开放期其中所有患者接受KANUMA在一个剂量1 mg/kg每隔周1次。开放延伸期间,用Kanuma治疗患者共至36周证实脂质参数改善,包括LDL-c和HDL-c水平,和ALT。
16 如何供应/贮存和处置
KANUMA 20 mg/10 mL小瓶以无菌,无防腐剂,无热原溶液在一次性,玻璃小瓶供应。
NDC 25682-007-01:20 mg/10 mL小瓶
KANUMA贮存在冰箱2°C至8°C(36°F至46°F)间在原始纸盒中避光保护。不要摇晃或冻结小瓶。
17 患者咨询资料
超敏性反应,包括过敏反应
忠告患者和护理人员在KANUMA治疗期间和后可能发生与给药和输注相关反应,包括威胁生命过敏反应和严重超敏性反应。告知患者过敏反应和超敏性反应的体征和症状,和发生体征和症状应立即寻求医疗护理[见警告和注意事项(5.1)
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use KANUMA safely and effectively. See full prescribing information for KANUMA.
KANUMA (sebelipase alfa) injection, for intravenous use Initial U.S. Approval: 2015
----------------------------INDICATIONS AND USAGE---------------------
KANUMA™ is a hydrolytic lysosomal cholesteryl ester and
triacylglycerol-specific enzyme indicated for the treatment of patients with a diagnosis of Lysosomal Acid Lipase (LAL) deficiency. (1)
----------------------DOSAGE AND ADMINISTRATION-----------------
PatientswithRapidlyProgressiveLALDeficiencyPresentingwithinthe First6MonthsofLife: The recommended starting dosage is 1 mg/kg as an intravenous infusion once weekly. For patients who do not achieve an optimal clinical response, increase to 3 mg/kg once weekly. (2.1)
Pediatric and Adult Patients with LAL Deficiency: The recommended dosage is 1 mg/kg as an intravenous infusion once every other week. (2.1)
Administration Instructions (2.3):
• Infuse over at least 2 hours.
• Consider further prolonging the infusion time for the 3 mg/kg dose or if a hypersensitivity reaction occurs.
• Consider a 1-hour infusion for the 1 mg/kg dose in patients who tolerate the infusion.
---------------------DOSAGE FORMS AND STRENGTHS----------------
Injection: 20 mg/10 mL (2 mg/mL) solution in single-use vials. (3)
-----------------------WARNINGS AND PRECAUTIONS------------------
• HypersensitivityReactionsincludingAnaphylaxis: Observe patients during and after the infusion. Consider interrupting the infusion or lowering the infusion rate, based on the severity of the reaction. If a severe hypersensitivity reaction occurs, immediately stop the infusion and initiate appropriate treatment. Pre-treatment with antipyretics and/or antihistamines may prevent subsequent reactions in those cases where symptomatic treatment is required. (5.1)
• HypersensitivitytoEggsorEggProducts: Consider the risks and benefits of treatment in patients with known systemic hypersensitivity reactions to eggs or egg products. (5.2)
------------------------------ADVERSE REACTIONS-------------------------
The most common adverse reactions are:
• PatientswithRapidlyProgressiveDiseasePresentingwithintheFirst6 MonthsofLife (≥30%): diarrhea, vomiting, fever, rhinitis, anemia, cough, nasopharyngitis, and urticaria. (6.1)
• PediatricandAdultPatients (≥8%): headache, fever, oropharyngeal pain, nasopharyngitis, asthenia, constipation, and nausea. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Alexion at 1-844-259-6783 or FDA at 1-800-FDA-1088
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 12/2015
---------------------------CONTRAINDICATIONS---------------------------
None. (4)
_
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Dosage
2.2 Preparation Instructions
2.3 Administration Instructions
2.4 Storage of Diluted Solution
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Hypersensitivity Reactions Including Anaphylaxis
5.2 Hypersensitivity to Eggs or Egg Products
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Immunogenicity
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.4 Pediatric Use
8.5 Geriatric Use
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
14 CLINICAL STUDIES
14.1 Patients with Rapidly Progressive LAL
Deficiency Presenting within the First 6 Months of Life
14.2 Pediatric and Adult Patients with LAL
Deficiency
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not listed.
1 INDICATIONS AND USAGE
KANUMA™ is indicated for the treatment of patients with a diagnosis of Lysosomal Acid Lipase (LAL) deficiency.
2 DOSAGE AND ADMINISTRATION
2.1 Dosage
PatientswithRapidlyProgressiveLALDeficiencyPresentingwithintheFirst6MonthsofLife:
The recommended starting dosage is 1 mg/kg administered once weekly as an intravenous infusion. For patients who do not achieve an optimal clinical response, increase to 3 mg/kg once weekly.
PediatricandAdultPatientswithLALDeficiency:
The recommended dosage is 1 mg/kg administered once every other week as an intravenous infusion.
2.2 Preparation Instructions
KANUMA is for intravenous infusion only. Prepare KANUMA using the following steps.
1. Determine the number of vials needed based on the patient’s weight and the recommended dose of 1 mg/kg or 3 mg/kg, using the following calculations (a-b):
a. Total dose (mg) = Patient’s weight (kg) x Recommended dose (mg/kg)
b. Total number of vials = Total dose (mg) divided by 20 mg/vial
2. Round to the next whole vial and remove the required number of vials from the refrigerator to allow them to reach room temperature.
a. Volume (mL) of calculated total dose = Total dose (mg) divided by the 2 mg/mL concentration
b. Volume (mL) of 0.9% Sodium Chloride for dilution = Total infusion volume (mL) for patient’s weight (see Table 1) – Volume (mL) of calculated total dose
Weight Range (kg) |
1 mg/kg dose |
3 mg/kg dose** |
Total Infusion Volume (mL) |
Total Infusion Volume (mL) |
|
1 to 10.9 |
10 |
25 |
11 to 24.9 |
25 |
50 |
25 to 49.9 |
50 |
100 |
50 to 99.9 |
100 |
250 |
100 to 120.9 |
250 |
500 |
* The infusion volume should be based on the prescribed dose and should be prepared to a final
KANUMA concentration of 0.1 mg/mL to 1.5 mg/mL.
** For patients with LAL deficiency presenting within the first 6 months of life who do not achieve an optimal clinical response with a dose of 1 mg/kg.
3. Mix gently by inversion. Do not shake the vials or the prepared infusion.
4. The solution should be inspected visually for particulate matter and discoloration prior to administration. The solution should be a clear to slightly opalescent, colorless to slightly colored solution. Thin, translucent particles or fibers may be present in the vials or diluted solution. Do not use if the solution is cloudy or if other particulate matter is observed.
5. Vials are for single-use only. Discard any unused product. Do not freeze.
2.3 Administration Instructions
Administer the diluted solution as an intravenous infusion using a low-protein binding infusion set with an in-line, low-protein binding 0.2 micron filter.
Infuse over at least 2 hours. Consider further prolonging the infusion time for patients receiving the 3 mg/kg dose or those who have experienced hypersensitivity reactions [see Warnings and Precautions (5.1)]. A 1-hour infusion may be considered for those patients receiving the 1 mg/kg dose who tolerate the infusion.
2.4 Storage of Diluted Solution
KANUMA contains no preservatives; therefore, product should be used immediately after dilution. If immediate use is not possible, the diluted product may be stored up to 24 hours in the refrigerator at 2°C to 8°C (36°F to 46°F). Do not freeze or shake. Protect from light.
3 DOSAGE FORMS AND STRENGTHS
Injection: 20 mg/10 mL (2 mg/mL) solution in single-use vials.
None.
5 WARNINGS AND PRECAUTIONS
5.1 Hypersensitivity Reactions Including Anaphylaxis
Hypersensitivity reactions, including anaphylaxis, have been reported in KANUMA-treated patients. In clinical trials, 3 of 106 (3%) patients treated with KANUMA experienced signs and symptoms consistent with anaphylaxis. These patients experienced reactions during infusion with signs and symptoms including chest discomfort, conjunctival injection, dyspnea, generalized and itchy rash, hyperemia, swelling of eyelids, rhinorrhea, severe respiratory distress, tachycardia, tachypnea, and urticaria. Anaphylaxis has occurred as early as the sixth infusion and as late as 1 year after treatment initiation.
In clinical trials, 21 of 106 (20%) KANUMA-treated patients, including 9 of 14 (64%) infants and 12 of 92 (13%) pediatric patients, 4 years and older, and adults, experienced signs and symptoms either consistent with or that may be related to a hypersensitivity reaction. Signs and symptoms of hypersensitivity reactions, occurring in two or more patients, included abdominal pain, agitation, fever, chills, diarrhea, eczema, edema, hypertension, irritability, laryngeal edema, nausea, pallor, pruritus, rash, and vomiting. The majority of reactions occurred during or within 4 hours of the completion of the infusion. Patients were not routinely pre-medicated prior to infusion of KANUMA in these clinical trials.
Due to the potential for anaphylaxis, appropriate medical support should be readily available when KANUMA is administered. If anaphylaxis occurs, immediately discontinue the infusion and initiate appropriate medical treatment. Observe patients closely during and after the infusion. Inform patients of the signs and symptoms of anaphylaxis, and instruct them to seek immediate medical care should signs and symptoms occur.
The management of hypersensitivity reactions should be based on the severity of the reaction and may include temporarily interrupting the infusion, lowering the infusion rate, and/or treatment with antihistamines, antipyretics, and/or corticosteroids. If interrupted, the infusion may be resumed at a slower rate with increases as tolerated. Pre-treatment with antipyretics and/or antihistamines may prevent subsequent reactions in those cases where symptomatic treatment
was required. If a severe hypersensitivity reaction occurs, immediately discontinue the infusion and initiate appropriate medical treatment.
Consider the risks and benefits of re-administering KANUMA following a severe reaction. Monitor patients, with appropriate resuscitation measures available, if the decision is made to re- administer the product.
5.2 Hypersensitivity to Eggs or Egg Products
KANUMA is produced in the egg whites of genetically engineered chickens. Patients with a known history of egg allergies were excluded from the clinical trials. Consider the risks and benefits of treatment with KANUMA in patients with known systemic hypersensitivity reactions to eggs or egg products.
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
In clinical trials, a total of 106 patients received treatment with KANUMA. The data described below reflect exposure to KANUMA in 75 patients who received KANUMA at dosages up to 3 mg/kg once weekly in clinical trials:
• Nine patients (5 males, 4 females) who had growth failure or other evidence of rapidly progressive LAL deficiency presenting within the first 6 months of life received KANUMA for up to 165 weeks (median 60 weeks) at escalating doses ranging between
0.35 mg/kg and 5 mg/kg once weekly[see Clinical Studies (14.1)]. The recommended initial dosage for these patients is 1 mg/kg escalating to 3 mg/kg once weekly[see Dosage and Administration (2.1)].
• 66 pediatric and adult patients with LAL deficiency aged 4 to 58 years (33 males, 33 females) received KANUMA 1 mg/kg every other week up to 36 weeks.
Table 2 summarizes the most common adverse reactions occurring in >30% of patients with rapidly progressive LAL deficiency presenting within the first 6 months of life receiving KANUMA.
Table 2: Most Common Adverse Reactions* in Patients with Rapidly Progressive LAL Deficiency Presenting within the First 6 Months of Life
Adverse Reactions |
KANUMA N=9 |
n (%) |
|
Diarrhea |
6 (67) |
Vomiting |
6 (67) |
Fever |
5 (56) |
Rhinitis |
5 (56) |
Anemia |
4 (44) |
Cough |
3 (33) |
Nasopharyngitis |
3 (33) |
Urticaria |
3 (33) |
* Reported in more than 30% of patients receiving KANUMA
Other less common adverse reactions reported in patients with rapidly progressive disease presenting within the first 6 months of life who received KANUMA included hypotonia, decreased oxygen saturation, retching, sneezing, and tachycardia.
Table 3 summarizes the most common adverse reactions that occurred in ≥8% of pediatric and adult patients with LAL deficiency receiving KANUMA at a dosage of 1 mg/kg once every other week during the 20-week double-blind treatment period [see Clinical Studies (14.2)].
Table 3: Most Common Adverse Reactions* in Pediatric and Adult Patients with LAL Deficiency
Adverse Reactions |
KANUMA N = 36 |
Placebo N = 30 |
n (%) |
n (%) |
|
Headache |
10 (28) |
6 (20) |
Fever |
9 (25) |
7 (23) |
Oropharyngeal pain |
6 (17) |
1 (3) |
Nasopharyngitis |
4 (11) |
3 (10) |
Asthenia |
3 (8) |
1 (3) |
Constipation |
3 (8) |
1 (3) |
Nausea |
3 (8) |
2 (7) |
* Reported in at least 8% of pediatric and adult patients receiving KANUMA and at a higher incidence
than in patients receiving placebo
Other less common adverse reactions reported in pediatric and adult patients who received KANUMA included anxiety and chest discomfort.
Hyperlipidemia
Increases in circulating LDL-cholesterol (LDL-c) and triglycerides above pre-treatment values were observed in 29 of 36 (81%) and 21 of 36 (58%) patients, respectively, at 2 and 4 weeks following initiation of KANUMA [see Clinical Pharmacology (12.2)]. The maximum mean percentage increase was 18% for LDL-c at Week 2 and 5% for triglycerides at Week 4.
As with all therapeutic proteins, there is potential for immunogenicity. Patients have developed anti-drug antibodies (ADA) to KANUMA. Immunogenicity assay results are highly dependent on the sensitivity and specificity of the assay and may be influenced by several factors such as: assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to KANUMA with the incidence of antibodies to other products may be misleading.
PatientswithRapidlyProgressiveLALDeficiencyPresentingwithintheFirst6MonthsofLife Seven of the 9 infants with rapidly progressive disease had at least one post-treatment ADA assessment, and 4 of these 7 (57%) patients developed ADA during treatment with KANUMA. Two of the 4 ADA-positive patients were determined to be positive for neutralizing antibodies that inhibit in vitro enzyme activity and cellular uptake of the enzyme. At the time of initial ADA positivity, 3 patients were receiving a dosage of 1 mg/kg once weekly and 1 patient was receiving a dosage of 3 mg/kg once weekly. Three of the 4 ADA-positive patients had ADA titers monitored from the initiation of treatment, and developed measureable ADA titers within the first 2 months of exposure. One of the 4 ADA-positive patients had persistent ADA titers. ADA titers decreased to undetectable levels in the remaining 3 patients while receiving continued treatment at a dosage of 3 mg/kg once weekly.
Hypersensitivity reactions occurred in all 4 of the ADA-positive patients, whereas they occurred in only 1 of the 3 ADA-negative patients. None of the patients discontinued treatment. In 1 patient, decreased growth velocity in a setting of neutralizing antibodies to KANUMA was observed.
PediatricandAdultPatientswithLALDeficiency
Five of 35 (14%) KANUMA-treated pediatric and adult patients who completed the 20-week double-blind period of study treatment developed ADA. All patients were receiving 1 mg/kg once every other week. All 5 ADA-positive patients first developed measurable ADA titers within the first 3 months of exposure. Two of the 5 ADA-positive patients had a measurable ADA titer at only one time point. In the 3 patients with measurable ADA titers at multiple time points, ADA titers decreased to undetectable levels during continued treatment. Two patients developed in vitro neutralizing antibodies during the open-label extension phase after 20 weeks and 52 weeks of treatment with KANUMA, respectively. There is no clear association between the development of ADA and decreased efficacy in pediatric and adult patients treated with KANUMA.
8.1 Pregnancy
RiskSummary
There are no available data on KANUMA in pregnant women to inform any drug-associated risk. Animal reproductive studies conducted with sebelipase alfa showed no evidence of embryolethality, fetotoxicity, teratogenicity, or abnormal early embryonic development at dosages up to 164 and 526 times the human dosage of 1 mg/kg every other week (based on AUC) in rats and rabbits, respectively.
The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
AnimalData
Sebelipase alfa administered during the period of organogenesis to rats (on gestation days 6, 9, 12, 15 and 17) and rabbits (on gestation days 7, 10, 13, 16 and 19) at intravenous doses up to 60 and 50 mg/kg, respectively, (approximately164 and 526 times the human AUC of 1387 ng.h/mL at 1 mg/kg dose administered once every other week, respectively) did not cause any adverse effects on embryofetal development. A pre- and postnatal development study in rats showed no evidence of adverse effects on pre- and postnatal development at intravenous doses
(administered on gestation days 6, 9, 12, 15, 18, and 20 and days 4, 7, 10, 14, and 17 postpartum) of sebelipase alfa up to 60 mg/kg/day (approximately 164 times the human AUC of 1387 ng.h/mL at 1 mg/kg dose administered once every other week).
8.2 Lactation
RiskSummary
There are no data on the presence of sebelipase alfa in human milk, the effects on the breastfed infant, or the effects on milk production. It is not known if sebelipase alfa is present in animal milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for KANUMA and any potential adverse effects on the breastfed infant from sebelipase alfa or from the underlying maternal condition.
8.4 Pediatric Use
Safety and effectiveness of KANUMA have been established in pediatric patients aged 1 month and older. Clinical trials with KANUMA were conducted in 56 pediatric patients (range 1 month to <18 years old) [see Clinical Studies (14)].
Clinical trials of KANUMA did not include any patients aged 65 years old and older. It is not known whether they respond differently than younger patients.
11 DESCRIPTION
KANUMA (sebelipase alfa) is a recombinant human lysosomal acid lipase (rhLAL). Lysosomal acid lipase (EC 3.1.1.13) is a lysosomal glycoprotein enzyme that catalyzes the hydrolysis of cholesteryl esters to free cholesterol and fatty acids and the hydrolysis of triglycerides to glycerol and free fatty acids.
KANUMA is produced by recombinant DNA technology in the egg white of eggs laid by genetically engineered chickens. Purified sebelipase alfa is a monomeric glycoprotein containing 6 N-linked glycosylation sites and has a molecular mass of approximately 55,000 daltons. The amino acid sequence for sebelipase alfa is the same as the amino acid sequence for human LAL. The specific activity of sebelipase alfa is 195 to 345 units/mg. One unit is the
amount of enzyme activity that catalyzes the hydrolysis of 1 micromole of the synthetic substrate 4-methylumbelliferyl oleate per minute at 37°C under specified assay conditions.
KANUMA is supplied as a sterile, preservative-free, non-pyrogenic aqueous solution in single- use vials for intravenous infusion. Each vial contains sebelipase alfa 20 mg/10 mL. Each mL of solution contains sebelipase alfa (2 mg), citric acid monohydrate (1.57 mg), Human Serum Albumin (10 mg), and trisodium citrate dihydrate (13.7 mg) at pH 5.9.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
LAL deficiency is an autosomal recessive lysosomal storage disorder characterized by a genetic defect resulting in a marked decrease or loss in activity of the lysosomal acid lipase (LAL) enzyme. The primary site of action of the LAL enzyme is the lysosome, where the enzyme normally causes the breakdown of lipid particles including LDL-c. Deficient LAL enzyme activity results in progressive complications due to the lysosomal accumulation of cholesteryl esters and triglycerides in multiple organs, including the liver, spleen, intestine, and the walls of blood vessels. The resulting lipid accumulation in the liver may lead to increased liver fat content and progression of liver disease, including fibrosis and cirrhosis. Lipid accumulation in the intestinal wall leads to malabsorption and growth failure. In parallel, dyslipidemia due to impaired degradation of lysosomal lipid is common with elevated LDL-c and triglycerides and low HDL-cholesterol (HDL-c).
Sebelipase alfa binds to cell surface receptors via glycans expressed on the protein and is subsequently internalized into lysosomes. Sebelipase alfa catalyzes the lysosomal hydrolysis of cholesteryl esters and triglycerides to free cholesterol, glycerol and free fatty acids.
12.2 Pharmacodynamics
In clinical trials, after initiation of dosing with KANUMA, breakdown of accumulated lysosomal lipid led to initial increases in LDL-c and triglycerides within the first 2 to 4 weeks of treatment. In general, following increases in LDL-c and triglycerides, these parameters decreased to below pre-treatment values within 8 weeks of treatment with KANUMA.
In all patients with elevated alanine aminotransferase (ALT) values at baseline (82 of 84 patients in clinical trials), reductions in ALT values were observed, generally within 2 weeks after initiation of treatment with KANUMA. Treatment interruption resulted in increases in LDL-c and ALT values and decreases in HDL-c.
12.3 Pharmacokinetics
The pharmacokinetic profile of sebelipase alfa was nonlinear with a greater than dose- proportional increase in exposure between 1 and 3 mg/kg based on non-compartmental analysis of data from 26 adults. No accumulation was observed following once weekly or once every other week dosing.
Using a population pharmacokinetic model, sebelipase alfa pharmacokinetic parameters were estimated for 65 pediatric and adult patients who received intravenous infusions of KANUMA at 1 mg/kg at Week 22 (Table 4); 24 patients were 4 to 11 years old, 23 were 12 to 17 years old, and 18 were adults. The pharmacokinetic profiles of sebelipase alfa were similar between adolescents and adults. The Tmax and T1/2 were similar across all age groups.
Table 4: Mean (SD) Pharmacokinetics Parameters at Week 22in Pediatric and Adult Patients Receiving 1 mg/kg Once Every Other Week
Parameter |
4-11 years old |
12-17 years old |
≥18 years old |
N=24 |
N=23 |
N=18 |
|
AUC (ng∙hr/mL) |
942 (388) |
1454 (699) |
1861 (599) |
Cmax (ng/mL) |
490 (205) |
784 (480) |
957 (303) |
Tmax (hr) |
1.3 (0.6) |
1.1 (0.3) |
1.3 (0.6) |
CL (L/hr) |
31.1 (7.1) |
37.4 (12.4) |
38.2 (12.5) |
Vc (L) |
3.6 (3.0) |
5.4 (2.4) |
5.3 (1.6) |
T1/2 (min) |
5.4 (4.3) |
6.6 (3.7) |
6.6 (3.7) |
Parameter values were estimated using a population pharmacokinetic model.
AUC = Area under the plasma concentration time curve. Cmax = Maximum concentration. Tmax = Time to maximum concentration. CL = Clearance. Vc = Central volume of distribution. T1/2 = Half-life.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic potential have not been performed with sebelipase alfa. Sebelipase alfa at intravenous doses up to 60 mg/kg administered twice weekly (approximately 164 times the human AUC of 1387 ng.h/mL at 1 mg/kg dose administered once every other week ) was found to have no adverse effect on fertility and reproductive performance of male and female rats.
13.2 Animal Toxicology and/or Pharmacology
In a rat disease model of LAL deficiency that exhibits several abnormalities analogous to the human disease, sebelipase alfa administered intravenously at dosages up to 3 mg/kg once weekly showed improvements in survival, body weight gain, organ weight reduction, reduction in serum transaminases (ALT and aspartate aminotransferase [AST]), reduction in serum and hepatic lipids, and improvement in liver histopathology.
14 CLINICAL STUDIES
14.1 Patients with Rapidly Progressive LAL Deficiency Presenting within the First 6 Months of Life
A multicenter, open-label, single-arm clinical study of KANUMA was conducted in 9 infants with LAL deficiency who had growth failure or other evidence of rapidly progressive disease prior to 6 months of age. The age range at entry was 1 to 6 months. Patients received KANUMA at 0.35 mg/kg once weekly for the first 2 weeks and then 1 mg/kg once weekly. Due to suboptimal clinical response, doses in all 6 surviving patients were escalated to 3 mg/kg once weekly, between 4 and 88 weeks (median 11 weeks) after starting treatment at 1 mg/kg. In one patient, the dose was escalated to 5 mg/kg once weekly at Week 88 due to decreased growth velocity in a setting of positive neutralizing anti-drug antibodies to KANUMA. The recommended dosage for these patients is 1 mg/kg to 3 mg/kg once weekly [see Dosage and Administration (2.1)].
Efficacy of KANUMA was assessed by comparing the survival of 9 KANUMA-treated patients at 12 months of age with an untreated historical cohort of 21 patients with a similar age at disease presentation and clinical characteristics. Of the 9 KANUMA-treated infants, 6 patients survived beyond 12 months of age, compared to 0 of 21 patients in the historical cohort, all of whom died by 8 months of age. The median age of the 6 surviving KANUMA-treated patients was 18.1 months (range 12 to 42.2 months).
Following initiation of treatment with KANUMA 1 mg/kg once weekly, weight-for-age z-scores improved in 3 of 5 surviving patients with growth failure, and all 6 surviving patients demonstrated improvements in weight-for-age z-scores following dose escalation to 3 mg/kg once weekly.
14.2 Pediatric and Adult Patients with LAL Deficiency
The safety and efficacy of KANUMA were assessed in 66 pediatric and adult patients with LAL deficiency, aged 4 to 58 years (71% were less than 18 years old), in a multicenter, double-blind, placebo-controlled trial. Patients were randomized to receive KANUMA at a dosage of 1 mg/kg (n=36) or placebo (n=30) once every other week for 20 weeks in the double-blind period. Sixty- two of the 66 (94%) patients had LDL-c of 130 mg/dL or greater at study entry. The majority of patients (58%) had LDL-c above 190 mg/dL at study entry, and 24% of patients with LDL-c above 190 mg/dL remained on lipid lowering medications.
At the completion of the 20-week double-blind period of the trial, a statistically significant improvement in percent change from baseline in LDL-c was observed in the KANUMA-treated group as compared to the placebo group (mean difference and 95% C.I.: -22%, [-33%, -15%]; p<0.0001). LDL-c of less than 130 mg/dL was achieved in 13 of 32 (41%; 95% C.I.: [24%,
58%]) KANUMA-treated patients and in only 2 of 30 (7%; 95% C.I.: [0%, 16%]) placebo- treated patients with baseline LDL-c of 130 mg/dL or greater. A statistically significant improvement in percent change from baseline at 20 weeks was also observed in the KANUMA- treated group compared to the placebo group for other parameters related to LAL deficiency, including decreases in non-HDL-c (mean difference and 95% C.I.: -21%, [-30%, -15%];
p<0.0001) and triglycerides (mean difference and 95% C.I.: -14%, [-28%, -1%]; p=0.0375), and increases in HDL-c (mean difference and 95% C.I.: 20%, [12%, 26%]; p<0.0001). The effect of KANUMA on cardiovascular morbidity and mortality has not been established.
Patients treated with KANUMA had larger reductions from baseline in ALT values and liver fat content (measured by MRI), compared to patients treated with placebo. The significance of these findings as they relate to progression of liver disease in LAL deficiency has not been established.
Open-labelExtension
Pediatric and adult patients who participated in the randomized, placebo-controlled trial were eligible to continue treatment in an open-label extension. Sixty-five of 66 patients (98%) entered the open-label period in which all patients received KANUMA at a dosage of 1 mg/kg once every other week. During the open-label extension, patients treated with KANUMA for up to 36
weeks demonstrated improvements in lipid parameters, including LDL-c and HDL-c levels, and ALT.
16 HOW SUPPLIED/STORAGE AND HANDLING
KANUMA 20 mg/10 mL vials are supplied as a sterile, preservative-free, nonpyrogenic solution in single-use, glass vials.
NDC 25682-007-01: 20 mg/10 mL vial
Store KANUMA under refrigeration between 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do not shake or freeze the vials.
17 PATIENT COUNSELING INFORMATION
HypersensitivityReactions,includingAnaphylaxis
Advise patients and caregivers that reactions related to administration and infusion may occur during and after KANUMA treatment, including life-threatening anaphylaxis and severe hypersensitivity reactions. Inform patients of the signs and symptoms of anaphylaxis and hypersensitivity reactions, and have them seek immediate medical care should signs and symptoms occur [see Warnings and Precautions (5.1)].
Manufactured by:
Alexion Pharmaceuticals Inc. Cheshire, CT 06410
US License Number: 1743 1-888-765-4747 (phone)
KANUMA is a trademark of Alexion Pharmaceuticals Inc.