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药品介绍 

拜耳制药公司宣布美国FDA日前批准了该公司的Kogenate FS（重组人凝血Ⅷ因子）上市，该药可用于0～16岁重度A型血友病患者的出血预防，能降低病人出血和关节损伤的几率。Kogenate FS的批准上市为这些患者提供了第Ⅷ因子，Kogenate FS作为常规用药，其安全性和有效性得到了FDA的认可，并为国家血友病基金医学科学咨询委员会（MASAC）所推荐。

成份: 重组人凝血因子VIII Recombinant Coagulation Factor VIII

适应症
本品用于血浆凝血因子VIII（FVIII）缺乏的甲型血友病治疗。在纠正或预防出血、急诊或择期手术中，本品起到暂时代替缺失的凝血因子的作用。

用法用量
在瓶签上本品用国际单位标示rFVIII（重组人凝血因子VIII）的效价，其效价用一期法测定。复溶后的药物必须在药物溶解后3小时内注射完毕。建议使用包装内提供的静脉注射用器具。
一般性治疗方法和疗效评估 ：下述剂量提供了一般性指导原则。须强调的是不同患者达到止血所需要的本品剂量各不相同，应视患者的需要、FVIII缺乏的严重程度、出血的严重程度、抗体存在的情况和期望达到的FVIII水平而定。治疗时监控患者的FVIII尤为重要。FVIII水平为疗效评估的重要因素。为达到满意疗效，必要时使用剂量可高于计算值。如果按公式计算的剂量注射后未达到预期的FVIII水平，或出血未得到控制，应怀疑患者体内是否存在抗体。通过实验室检查可检测和定量抗体。存在抗体时，不同患者所需的FVIII剂量差异较大，可根据疗效优化治疗方案。某些低抗体滴度(<10 BU)的患者应用FVIII制剂成功治疗后，并未产生免疫记忆应答抗体滴度升高。通过评估FVIII的水平和临床疗效进行适宜治疗。对FVIII产生记忆应答或具有高滴度抗体的患者，必要时可选择其他治疗药物，如凝血因子IX复合物制剂、抗血友病因子（猪源性）、重组激活凝血因子VIIa或抗抑制剂凝血因子复合物。

剂量计算 ：体内FVIII水平升高的百分比可用每公斤体重注射本品的剂量（IU/kg）乘以每公斤体重每个单位的2%(2%/IU/kg)计算而得。计算方法依据血浆FVIII和重组AHF在临床使用的剂量，下面
举例说明 ：
预计的FVIII升高值(%) = #注射单位×2%/IU/kg<246>体重(kg) 70 kg的成年人 = 1400 IU×2%/IU/kg<246>70 kg
或者 ：
需要的剂量(IU)= 体重(kg)×预计的FVIII升高值% <246>2%/IU/kg
15 kg的儿童 = 15 kg×100%<246>2%/IU/kg = 750 IU

参照下述指导原则，根据出血的类型和严重程度计算到达止血所需要的注射剂量。

轻微出血（表层出血、早期出血、出血到关节） - 治疗所需的血浆活性FVIII水平为20-40% ：维持治疗血浆中水平的必要剂量为10-20 IU/kg，如进一步出血，按上述剂量再次注射 ；

中等出血（肌肉、口腔、关节出血和外伤）\手术（小手术） - 治疗所需的血浆活性FVIII水平为30-60% ：维持治疗血浆中水平的必要剂量为15-30 IU/kg，必要时，在12-24小时之间再按上述剂量注射1次 ；

危及到生命的出血（颅内、腹内或胸廓内出血、胃肠出血、中枢神经系统出血、咽后或腹膜后或髂腰肌膜出血）骨折颅部外伤 - 治疗所需的血浆活性FVIII水平为80-100% ：维持治疗血浆中水平的必要剂量为开始给予40-50 IU/kg，每8-12小时按20-25 IU/kg注射1次 ；

手术（较大的外科手术） - 治疗所需的血浆活性FVIII水平大约为100% ：维持治疗血浆中水平的必要剂量为术前给予50 IU/kg，并确定FVIII活性100%，必要时，开始注射6-12小时后，按上述剂量重复注射持续10-14天，直至痊愈。 预防 ：正如Nilsson等人报道，AHF（抗血友病因子）浓缩剂定期注射可预防出血。

药物过量 目前尚无药物过量的报道。如怀疑药物过量，密切注意不良反应并采取适当的措施。

禁忌
对该产品不耐受或有过敏反应者 ；对鼠或仓鼠蛋白过敏者禁用。

注意事项
本品用于治疗FVIII缺乏的出血障碍。注射本品之前，应确诊患者FVIII缺乏。
甲型血友病患者接受治疗后，可能会产生FVIII的中和抗体，尤其是严重的血友病患儿在治疗的第1年内，或曾用少量FVIII治疗的任何年龄患者，产生抗体的情况尤为常见。甲型血友病患者在治疗的任何时间都有可能产生抗体。根据血友病治疗中心的建议，对接受任何FVIII浓缩剂治疗的患者，包括本品，须通过临床观察和实验室检测密切监控患者FVIII抗体产生的情况。
文献报道应用抗血友病因子浓缩剂治疗的患者中，可产生下述症状：低血压、风疹、胸部压迫感伴过敏反应。也有报道应用前一代产品KOGENATE 发生变态和过敏反应，但非常罕见，主要发生在儿童和曾接受过其他FVIII浓缩剂治疗的患者中（详见不良反应-上市后经验）。严重的过敏反应须采取紧急抢救措施如注射肾上腺素和吸氧。
产生鼠或仓鼠蛋白的抗体 ：临床研究中观察了患者是否对鼠或仓鼠蛋白产生血清学反应。结果表明未发现患者对这些蛋白产生特异性抗体，注射本品也未发现对动物蛋白的严重过敏反应。虽然未曾观察到这些过敏反应，但应意识到患者可能对鼠或仓鼠蛋白的过敏，应警惕过敏反应的早期症状（如荨麻疹、局部或全身风疹、哮喘和低血压）。如果发现这些症状，建议患者停止使用该产品，并应及时和医生联络。

本品不含血管性假性血友病因子(von Willebrands factor)，故不能用于血管性假性血友病的治疗。
本品复溶、注射和静脉注射用器具及针头的处理必须小心谨慎。经皮注射的针头如被血液污染可传染病毒包括HIV(AIDS)和肝炎。一旦发生损伤，应立即观察。一次性使用的针头用完后放入保护套中。静脉注射用的全部器具包括复溶后的本品均应废弃，按生物安全程序进行处理。

复溶 ：
操作前须清洗双手。

除去真空 ：
未开盖的稀释液和浓缩剂进行加温，温度不能超过37°C。
分别除去塑料顶盖后，酒精消毒橡胶塞。注意 ：千万不要打开橡胶塞。
去除双向针头一端的保护套，将针头刺入稀释液瓶的橡胶塞。
去除双向针头另一端的保护套，倒转稀释液瓶后，针头以一定的角度刺入浓缩剂瓶的橡胶塞。
浓缩剂瓶中的真空会把稀释液抽吸到瓶中。稀释液瓶以一定的角度对准浓缩剂瓶，以便稀释液直接射入到浓缩剂的瓶壁上。避免产生过多的气泡。如稀释液未抽吸到浓缩剂瓶中，说明瓶中真空不足，该瓶浓缩剂不能使用。
移去稀释液瓶和双向针头后轻摇，直到浓缩剂完全溶解，避免产生过多的气泡。
用酒精再次消毒复溶后的本品橡胶塞，在空气中自然干燥。
浓缩剂粉末全部溶解后，用包装中提供的带过滤针头的注射器把溶液吸入到注射器中。再用提供的静脉注射用器具替换过滤针头，进行静脉注射。注意 ：进行静脉穿刺应紧紧抓住一个翼或二个翼 ；此时不能使用针头护套。
如果同一患者注射量超过1瓶，在连接静脉注射针头之前，需分别用未使用过的一次性过滤针头将两瓶溶液抽吸入同一注射器中。
注射用溶液及容器在使用前须肉眼检查有无颗粒物质和颜色变化。

注射速度 ：注射速度应根据每个患者的反应，5-10分钟或更短时间注射完，患者的耐受性良好。

内容物 ：本品一次使用的包装含有以下内容物 ：适量的灭菌注射用水，灭菌的双向针头、灭菌的过滤针头和静脉注射用器具。 各种规格的稀释液均为2.5 mL。

儿童用药
对未接受过和接受过少量本品的患儿（n=62）已进行了安全性和有效性的研究。本品适用所有年龄的儿童，包括新生儿、婴儿、儿童和青少年。

老年患者用药
本品的临床研究中，由于65岁或65岁以上的患者例数不足，所以不能确定老年患者与年轻患者是否存在不同反应。然而根据KOGENATE和其他AHF产品的临床经验。老年和年轻患者之间并无差异。对接受本品的老年患者，根据每个人的情况而选择剂量。

孕妇及哺乳期妇女用药
未曾应用本品进行动物繁殖的研究。孕妇使用本品是否会引起胎儿损伤或影响生殖能力尚未明确。只有必需时，本品才能在妊娠和哺乳期应用。

不良反应
对曾接受治疗的患者（PTPs）进行了临床研究，注射4160次发生不良反应109例（占2.6%）。13例与药物至少有间接关系，另7例无法评估。因此在11个患者中发生的20例不良反应或无法评估，或至少与本品有间接关系，仅0.5%的不良反应与注射的药物有关系。与药物有间接关系的不良反应包括注射部位的局部反应（2例）、头晕（2例）、出疹（2例）、味觉改变（1例）、血压升高（1例）、瘙痒（1例）、人格解体（1例）、恶心（1例）和鼻炎（1例）。72名（PTPs）严重甲型血友病患者曾接受本品平均治疗54天，未产生FVIII抗体。
未曾接受治疗的患者(PUPs)和少量接受过治疗(MTP)的患儿临床研究中，18例不良反应至少可能与药物有关，其中8名患者因产生抗体而引发的并发症（前述临床药理部分的10名患者包括这8名患者） ：静脉穿刺前臂出血、便秘、腺病、出疹，1名患者出现贫血、面色苍白、胃肠炎和严重中耳炎。
上市后经验 ：下列不良反应主要来自于上市后经验和发表的文献，一般无法估计其准确的比例。接受前一代产品治疗的患者，尤其是年幼患者或以前接受过其他FVIII浓缩剂的患者，发生严重的变态反应和过敏反应病例非常罕见。个别患者会产生低血压。报道出现风疹也十分罕见。本品以蔗糖作配方，虽未报道这些严重的不良反应，但也可能会发生。曾有报道使用本品会产生呼吸困难的不良反应。

药物相互作用
目前尚未发现和其他药物存在药物相互作用。

FDA妊娠分级
C级: 动物研究证明药物对胎儿有危害性（致畸或胚胎死亡等），或尚无设对照的妊娠妇女研究，或尚未对妊娠妇女及动物进行研究。本类药物只有在权衡对孕妇的益处大于对胎儿的危害之后，方可使用。

贮藏/有效期
本品需冷藏(2-8°C)，遮光保存，禁止冷冻。从冷藏环境中取出后，请在小盒的相应位置记录取出日期，切勿再放回冷藏环境 ；该产品在有效期之前、25°C以下环境可存放3个月。 有效期24个月。

性状
本品主要成份为重组人凝血因子VIII，加入了蔗糖（0.9-1.3%）、甘氨酸（21-25 mg/mL）和组氨酸（18-23 mM）。产品中还含有氯化钙（2-3 mM）、钠(27-36 mEq/L)、氯(32-40 mEq/L)、聚山梨酯80(≤64-96 ug/mL)、咪唑(≤20 ug/1000 IU)、磷酸三丁酯(≤5 ug/1000 IU)和铜(≤0.6 ug/1000 IU)。 本品为白色或浅黄色干粉剂。

药理作用
本品采用重组DNA技术生产，其生物学活性与从血浆中提纯的FVIII相同，用于治疗传统的血友病(甲型血友病)。

【临床试验】：在北美和欧洲，71名严重甲型血友病患者参加了为期6个月的应用本品进行家庭治疗的研究，这些患者年龄为12-59岁，曾接受过其他重组FVIII和血浆抗血友病因子的治疗。该研究中共进行3995次静脉注射，共计7400000单位本品。研究期间治疗659次出血，共注射951次本品。多数情况下（89.5%）通过1次或2次注射就能成功止血，每次平均使用剂量约28 IU/kg。定期注射治疗占76%。有9名患者在11次手术中应用本品治疗，这些手术包括1例脑瘤切除术、2例膝盖置换术、2例关节滑膜切除术(其中1例伴跟腱拉长)、2例包皮环切术、1例疝气修补术和3例拔牙。所有病例显示了满意的止血效果。
临床研究中，本品被应用在未曾接受过治疗的出血患者（PUPs）和接受过少量治疗的儿童出血病例中(MTPs)。61例PUPs/MTPs接受本品的治疗。通过1次或2次静脉注射本品就能有效止血。其中10名患者产生了抗体，占15%。该研究中，约一半的患者治疗期在20天以上，产生抗体的情况与其他患儿使用血浆FVIII和重组FVIII时是一致的。

毒理研究
致癌、致突变和对生殖能力的损伤 ：对超剂量（远大于临床使用最高剂量）rFVIII的潜在致突变性进行了体外评价，未发现逆转突变和染色体畸变。对动物使用rFVIII进行了体内评价，其剂量是临床最高剂量的10-40倍，亦证明rFVIII不存在潜在的致突变作用。rFVIII在动物体内潜在致癌作用的长期观察未曾进行。

药代动力学
在北美对20名严重甲型血友病患者进行药代动力学研究。在与前一代产品KOGENATE药代动力学比较研究中，本品的结果与KOGENATE结果相似。本品注射10分钟后，FVIII平均恢复率为2.1±0.3%/IU/kg，KOGENATE为2.4±0.7%/IU/kg，两者无统计学差异（可信区间0.815-1.01）。本品平均生物学半衰期与KOGENATE相似，平均为13小时，与从血浆中提纯的抗血友病因子（AHF）半衰期相似。rFVIII和本品都能缩短活化部分凝血活酶时间。本品恢复率和半衰期在治疗的24周内没有改变，表明持续有效，无证据表明产生了FVIII抑制物。37例患者（用本品治疗24周后），一次注射本品10分钟后，FVIII平均恢复率为2.1%/IU/kg，与基线、治疗第4周和12周平均恢复率无显著改变。

*血友病是一种凝血因子Ⅷ或Ⅸ，由于缺乏或者功能异常引起的出血性遗传性疾病。其中Ⅷ因子缺乏称为甲型血友病，Ⅸ因子缺乏称为乙型血友病，患者需要终生治疗。其预防和治疗主要采用凝血因子的替代方法，由最初的新鲜全血、新鲜冰冻血浆、血浆冷沉淀成分、凝血因子浓缩物、高纯度凝血因子浓缩物发展到今天的重组人凝血因子。目前国内外已开展试验性基因治疗 医学教 育网收集整理 。
重组人凝血Ⅷ因子Kogenate-FS是采用BHK-21（Baby Hamster Kidney cell）宿主细胞表达的第二代重组基因工程产品，已在美国、欧洲等许多国家批准上市。Kogenate-FS由2351个氨基酸组成，含有25个N糖基化位点，为经糖基化修饰的人Ⅷ因子全长序列糖蛋白，是目前重组技术表达的分子量最大且具有特定生物活性的蛋白。生产工艺采用连续灌流发酵，发酵罐规模达200L，一个生产周期大约需要256天，目前在重组生物技术生产领域处于领先地位。 关于血源或者重组人凝血Ⅷ因子，医生和患者最关心两个问题：1）输注后抑制物的产生；2）产品的病原体安全性。由于输注后抑制物的产生会阻遏Ⅷ因子活性，直接影响到临床的长期使用，成为医生关注的重点。第一代重组产品Kogenate抑制物产生率约30%；对于第二代重组产品Kogenate-FS，从目前已完成的两项长期前瞻性小样本临床试验研究（满足至少随访2年和20个暴露日的要求）的初步统计资料分析，在既往未经治疗或者经过最低程度治疗的60例重度血友病婴儿和儿童（小于4岁）患者中，抑制物的产生率约15%，较第一代产品有显著降低。由于第二代产品已将原来成品中的人血白蛋白保护剂替换成甘氨酸，重组产品本身没有原料血浆的感染风险，因此从一定意义上极大降低了血源性病原体的安全性风险。但由于在生产过程的细胞培养阶段采用了人血白蛋白，仍难以完全排除尚未明确的血源病原体的感染风险性，目前正在研制无血清或者添加植物来源蛋白成分的培养方法。
ogenate-FS的生产过程需要连续培养BHK-21细胞，并使用了一些动物来源的培养成分，因此需要进行病毒灭活/去除工艺验证研究。以前对于血液制品的病毒灭活/去除工艺验证主要以指示病毒获得的试验结果，拜耳公司的病原体安全性专家重点介绍了以朊病毒（prion）为指示病原体进行的初步去除试验验证结果。从报告的数据分析，对于人血源制备的凝血因子生产工艺，模拟病原体主要伴随血浆组分III、Ⅳ被分离；对于重组制品，DEAE柱层析步骤则提示对于指示病原体具有一定的去除作用（降低2-3个对数级），但是否为有效的工艺步骤目前尚难以评价。在试验研究中对于模拟指示病原体的检测采用了生物和免疫印迹的方法。试验研究采用的模拟病原体是与人PrPvCJD行为类似的仓鼠（Hamster）PrPSc，由于PrPSc已适应了仓鼠细胞的感染，因此选择仓鼠进行了生物学检测。过去对于PrP的检测，由于动物试验周期和检测中使用的抗体特异性（难以鉴别正常和异常的PrP）等困难，使得验证研究报道不多。拜耳公司巧妙应用了正常PrP与模拟病原体PrP对于蛋白酶水解抗性的差异，解决了病原体检测特异性方面的难题并申报了相关的技术专利。因此，采用免疫印迹方法能够很快得到试验结果，这些试验对于今后开展深入研究具有重要参考价值

 

Kogenate FS

Generic Name: antihemophilic factor (recombinant)
Dosage Form: injection

Medically reviewed on Mar 1, 2018

 

 

 

Indications and Usage for Kogenate FSControl and Prevention of Bleeding Episodes

Kogenate® FS is an antihemophilic factor that is indicated for the control and prevention of bleeding episodes in adults and children (0-16 years) with hemophilia A.

 

Peri-operative Management

Kogenate FS is indicated for surgical prophylaxis in adults and children with hemophilia A.

Routine Prophylaxis in Children with Hemophilia A with No Pre-existing Joint Damage

Kogenate FS is indicated for routine prophylactic treatment to reduce the frequency of bleeding episodes and the risk of joint damage in children with no pre-existing joint damage.

Kogenate FS is not indicated for the treatment of von Willebrand’s disease.

 

 

Kogenate FS Dosage and Administration

For Intravenous Use After Reconstitution

· Treatment with Kogenate FS should be initiated under the supervision of a physician experienced in the treatment of hemophilia A.

· Each vial of Kogenate FS has the recombinant factor VIII (rFVIII) potency in international units stated on the label.

· Dosage and duration of treatment depend on the severity of the factor VIII deficiency, the location and extent of bleeding, and the patient’s clinical condition.1 Careful control of replacement therapy is especially important in cases of major surgery or life-threatening bleeding episodes. [See Table 1 and Table 2.]

The expected in vivo peak increase in factor VIII level expressed as IU/dL (or % normal) can be estimated using the following formulas:

Dosage (units) = body weight (kg) x desired factor VIII rise (IU/dL or % of normal) x 0.5 (IU/kg per IU/dL)

OR

IU/dL (or % normal)=Total Dose (IU)/body weight (kg) x 2 [IU/dL]/[IU/kg]

Examples (assuming patient’s baseline factor VIII level is <1% of normal):

1. A dose of 1750 IU Kogenate FS administered to a 70 kg patient should be expected to result in a peak post-infusion factor VIII increase of 1750 IU x {[2 IU/dL]/[IU/kg]}/[70 kg] = 50 IU/dL (50% of normal).

2. A peak level of 50% is required in a 15 kg child. In this situation, the appropriate dose would be:
50 IU/dL/{[2 IU/dL]/[IU/kg]} x 15 kg = 375 IU.

Doses administered should be titrated to the patient’s clinical response. Patients may vary in their pharmacokinetic (e.g., half-life, in vivo recovery) and clinical responses to Kogenate FS.2,3,4 Although the dose can be estimated by the calculations above, it is highly recommended that, whenever possible, appropriate laboratory tests including serial factor VIII activity assays be performed. [See Warnings and Precautions (5.4) and Clinical Pharmacology (12.3).]

Control and Prevention of Bleeding Episodes

The careful control of treatment dose is especially important in cases of life-threatening bleeding episodes or major surgery.

The following table can be used to guide dosing in bleeding episodes.

Table 1 Control and Prevention of Bleeding Episodes for Children and Adults
Type of Bleeding Episode	Factor VIII Level Required (IU/dL or % of normal)	Dosage and Frequency Necessary to Maintain the Therapeutic Plasma Level
Minor Early hemarthrosis, minor muscle or oral bleeds.	20–40	10–20 IU per kg Repeat dose if there is evidence of further bleeding.
Moderate Bleeding  into muscles, bleeding into the oral cavity, definite hemarthroses, and known trauma.	30–60	15–30 IU per kg Repeat dose every 12–24 hours until bleeding is resolved.
Major Gastrointestinal bleeding. Intracranial, intra-abdominal or intrathoracic bleeding, central nervous system bleeding, bleeding in the retropharyngeal or retroperitoneal spaces, or iliopsoas sheath. Fractures. Head trauma.	80–100	Initial dose 40–50 IU per kg Repeat dose 20–25 IU per kg every 8–12 hours until bleeding is resolved.

 

Peri-operative Management

The careful control of treatment dose is especially important in cases of major surgery or life-threatening bleeding episodes.

The following table can be used to guide dosing in surgery:

Table 2 Peri-operative Management for Adults and Children
Type of Surgery	Factor VIII Level Required (IU/dL or % of normal)	Dosage and Frequency Necessary to Maintain the Therapeutic Plasma Level
Minor Including tooth extraction	30–60	15–30 IU per kg Repeat dose every 12–24 hours until bleeding is resolved.
Major Examples include tonsillectomy, inguinal herniotomy, synovectomy, total knee replacement, craniotomy, osteosynthesis, trauma.	100	Pre-operative dose 50 IU per kg Verify 100% activity prior to surgery. Repeat as necessary after 6 to 12 hours initially, and for 10 to 14 days until healing is complete.

Routine Prophylaxis in Children with No Pre-existing Joint Damage. 

The recommended dose for routine prophylaxis is 25 IU/kg of body weight every other day.5

Instructions for Use

Kogenate FS is administered by intravenous (IV) injection after reconstitution. Patients should follow the specific reconstitution and administration procedures provided by their physicians.

For instructions, patients should follow the recommendations in the FDA-Approved Patient Labeling. [See FDA-Approved Patient Labeling (17).]

Reconstitution, product administration, and handling of the administration set and needles must be done with caution. Percutaneous puncture with a needle contaminated with blood can transmit infectious viruses including HIV (AIDS) and hepatitis. Obtain immediate medical attention if injury occurs. Place needles in a sharps container after single use. Discard all equipment, including any reconstituted Kogenate FS product, in an appropriate container.

Preparation and Reconstitution

The procedures below are provided as general guidelines for the reconstitution and administration of Kogenate FS with BIO-SET®, a needleless self-contained reconstitution system. Always work on a clean surface and wash hands before performing the following procedures.

Vacuum Transfer and Reconstitution

1. Warm the unopened diluent (as needed) and the concentrate to a temperature not to exceed 37°C or 99°F.

2. Remove the cap from the concentrate. Take out the prefilled diluent syringe and remove the tip cap. (Fig. A).

3. Connect the prefilled diluent syringe to the concentrate vial by gently screwing on to the BIO-SET connection (Fig. B).

4. Place the vial on a rigid, non-skid surface and hold it firmly with one hand. With the other hand, strongly press down the fingerplate near the syringe tip using your thumb and index finger (Fig. C) until the fingerplate meets the top edge of the BIO-SET. This confirms that the system is activated (Fig. D).

5. Grasp the plunger rod by the top plate and remove from carton. Avoid touching the sides and threads of the plunger rod. Immediately screw plunger rod into the syringe rubber stopper (Fig. E).

6. Inject the diluent into the concentrate by pushing down the plunger rod slowly (Fig. F).

7. Swirl gently until completely dissolved without creating excessive foaming (Fig. G).

8. Kogenate FS should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

9. Invert vial/syringe and transfer the solution into syringe that was used to deliver the diluent (Fig. H). Ensure that the entire contents of the reconstituted Kogenate FS vial are drawn into the syringe.

10. Unscrew the filled syringe to disconnect it from the empty concentrate vial (Fig. I).

11. Attach the filled syringe to the administration set provided and immediately inject intravenously (Fig. J). NOTE: See accompanying instructions for Infusion Set with Filter.

12. If the same patient is to receive more than one vial, the diluent syringe provided should be used to reconstitute the powder in the product vials as described above. The reconstituted solutions should then be combined in a larger plastic syringe (not provided) and administered as usual (Fig. J).

 

Administration

For Intravenous Use Only After Reconstitution

· Kogenate FS should be inspected visually for particulate matter and discoloration prior to administration, wherever solution and container permit. Turbid or discolored solution should be discarded.

· Reconstituted Kogenate FS may be stored at room temperature prior to administration, but is to be administered within 3 hours. It is recommended to use the IV administration set provided.

· A dose of Kogenate FS may be administered over a period of 1 to 15 minutes. The rate of administration however, should be adapted to the response of each individual patient. The pulse rate should be determined before and during administration of Kogenate FS. If there is a significant increase in pulse rate, reducing the rate of administration or temporarily halting the injection allows the symptoms to disappear promptly.

Dosage Forms and Strengths

Kogenate FS is available as a lyophilized powder in single use glass vials containing 250, 500, 1000, 2000, and 3000 International Units (IU).

Each vial of Kogenate FS is labeled with the recombinant antihemophilic factor activity expressed in IU per vial. This potency assignment employs a factor VIII concentrate standard that is referenced to a WHO International Standard for factor VIII concentrates, and is evaluated by appropriate methodology to ensure accuracy of the results.

Contraindications

Kogenate FS is contraindicated in patients who have manifested life-threatening immediate hypersensitivity reactions, including anaphylaxis, to the product or its components, including mouse or hamster proteins.

Warnings and PrecautionsGeneral

The clinical response to Kogenate FS may vary. If bleeding is not controlled with the recommended dose, the plasma level of factor VIII should be determined and a sufficient dose of Kogenate FS should be administered to achieve a satisfactory clinical response. If the patient’s plasma factor VIII level fails to increase as expected or if bleeding is not controlled after the expected dose, the presence of an inhibitor (neutralizing antibodies) should be suspected and appropriate testing performed. [See Warnings and Precautions (5.4).]

Anaphylaxis and Severe Hypersensitivity Reactions

Allergic-type hypersensitivity reactions including anaphylaxis have been reported with Kogenate FS and have manifested as pruritus, rash, urticaria, hives, facial swelling, dizziness, hypotension, nausea, chest discomfort, cough, dyspnea, wheezing, flushing, discomfort (generalized) and fatigue. Discontinue Kogenate FS if symptoms occur and seek immediate emergency treatment.

Kogenate FS contains trace amounts of mouse immunoglobulin G (MuIgG) and hamster (BHK) proteins. Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins.

Neutralizing Antibodies

Patients treated with antihemophilic factor (AHF) products should be carefully monitored for the development of factor VIII inhibitors by appropriate clinical observations and laboratory tests.6 Inhibitors have been reported following administration of Kogenate FS predominantly in previously untreated patients. If expected plasma factor VIII activity levels are not attained, or if bleeding is not controlled with an expected dose, an assay that measures factor VIII inhibitor concentration should be performed.[See Warnings and Precautions (5.4).]

Monitoring Laboratory Tests

· Monitor plasma factor VIII activity levels by the one-stage clotting assay to confirm the adequate factor VIII levels have been achieved and maintained, when clinically indicated. [See Dosage and Administration (2).]

· Monitor for development of factor VIII inhibitors. Perform assay to determine if factor VIII inhibitor is present. If expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with the expected dose of Kogenate FS. Use Bethesda Units ( BU) to titer inhibitors.

o If the inhibitor is less than 10 BU per mL, the administration of additional Kogenate FS concentrate may neutralize the inhibitor, and may permit an appropriate hemostatic response.

Adequate hemostasis may not be achieved if inhibitor titers are above 10 BU per mL. The inhibitor titer may rise following Kogenate FS infusion as a result of an anamnestic response to factor VIII. The treatment or prevention of bleeding in such patients requires the use of alternative therapeutic approaches and agents.

Adverse Reactions

The most serious adverse reactions are systemic hypersensitivity reactions including bronchospastic reactions and/or hypotension and anaphylaxis and the development of high-titer inhibitors necessitating alternative treatments to AHF.

The most common adverse reactions observed in clinical trials (frequency ≥ 4% of patients) are inhibitor formation in previously untreated patients (PUPs) and minimally treated patients (MTPs), skin-related hypersensitivity reactions (e.g., rash, pruritus), infusion site reactions (e.g., inflammation, pain), and central venous access device (CVAD) line-associated infections in patients requiring a CVAD for intravenous administration.

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 clinical trials of another drug and may not reflect the rates observed in clinical practice.

Previously Treated Patients (PTPs)

During the clinical studies conducted in PTPs, 451 adverse events (irrespective of the relationship to the study drug) were reported in the course of 24,936 infusions (1.8%). Twenty-four of the 451 adverse events were assessed as related to Kogenate FS (0.1%).

Adverse reactions reported by ≥ 4% of the patients are listed in Table 3 below.

Table 3 Adverse Reactions (AR) in Previously Treated Patients (PTPs) with Frequency of ≥ 4%
SOC = System Organ Class
MedDRA Primary SOC	Preferred Term	Total No. of Patients: 73 No. of Patients with AR (%)	Total No. of Infusions: 24,936 AR per Infusion (%)
Skin and Subcutaneous Tissue Disorders	Rash, pruritus	6 (8.2%)	0.02
General Disorders and Administration Site Conditions	Infusion site reactions	3 (4.1%)	0.01

Previously Untreated Patients (PUPs) and Minimally Treated Patients (MTPs)

In clinical studies with pediatric PUPs and MTPs, 726 adverse events were reported in the course of 9,389 infusions (7.7%). Twenty-nine of the 726 adverse events were assessed as related to Kogenate FS (0.3%).

Adverse reactions reported by ≥ 4% of the patients are listed in Table 4 below.

Table 4 Adverse Reactions (AR) in Previously Untreated Patients (PUPs) and Minimally Treated Patients (MTPs) with Frequency of ≥ 4% (Age Range 2-27 months)
SOC = System Organ Class
* *Denominator for de-novo inhibitors is N=60, since one patient had a pre-existing inhibitor.
MedDRA Primary SOC	Preferred Term	Total No. of patients: 61 No. of Patients with AR (%)	Total No. of Infusions: 9,389 AR per Infusion (%)
Skin and Subcutaneous Tissue Disorders	Rash, pruritus, urticaria	10 (16.4)	0.01
Blood and Lymphatic System Disorders	Factor VIII inhibition	9 (15)*	N/A
General Disorders and Administration Site Conditions	Infusion site reactions	4 (6.6)	0.04

Minimally Treated Patients (MTPs) in the Joint Outcome Study

In the Joint Outcome Study with pediatric MTPs treated with routine prophylaxis or episodic enhanced treatment for 5.5 years, 46 of the 65 randomized patients experienced adverse events over the study duration. Adverse events were not assessed for their relationship with Kogenate FS.

Table 5 Adverse Events (AE) in MTPs in the Joint Outcome Study (Age Range 0-6 years)
SOC = System Organ Class
* Three patients from the enhanced episodic arm had catheter removal.
MedDRA Primary SOC	Preferred Term	Total No. of Prophylaxis Arm Patients: 32 No. of Patients with AE (%)	Total No. of Enhanced Episodic Arm Patients: 33 No. of Patients with AE (%)
Surgical and Medical Procedures	Central venous catheterization, Catheter removal	19 (59)	18* (55)
Infections and Infestations	Central line infection	6 (19)	6 (18)
General Disorders and Administration Site Conditions	Pyrexia	1 (3)	4 (12)

Immunogenicity

In clinical studies with 73 PTPs (defined as having more than 100 exposure days), one patient had a pre-existing inhibitor. In the other 72 patients, followed over 4 years, no de-novo inhibitors were observed.

In clinical studies with pediatric PUPs and MTPs, inhibitor development was observed in 9 out of 60 patients (15%), 6 were high titer1 (>5BU) and 3 were low-titer inhibitors. Inhibitors were detected at a median number of 7 exposure days (range 2 to 16 exposure days).

In the Joint Outcome Study with Kogenate FS,5 de-novo inhibitor development was observed in 8 of 64 patients with negative baseline values (12.5%), 2 patients developed high titer1 (>5 BU) and were withdrawn from the study. Six patients developed low-titer inhibitors. Inhibitors were detected at a median number of 44 exposure days (range 5 to 151 exposure days).

Post-Marketing Experience

The following adverse reactions have been identified during post approval use of Kogenate FS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Among patients treated with Kogenate FS, cases of serious allergic/hypersensitivity reactions (which may include facial swelling, flushing, hives, blood pressure decrease, nausea, rash, restlessness, shortness of breath, tachycardia, tightness of the chest, tingling, urticaria, vomiting) have been reported, particularly in very young patients or patients who have previously reacted to other factor VIII concentrates.

The following table represents the post-marketing adverse reactions as MedDRA Preferred Terms.

Table 6 Post-Marketing Experience
SOC = System Organ Class
MedDRA Primary SOC	Preferred Term
Blood and Lymphatic System Disorders	FVIII inhibition
Skin and Subcutaneous Tissue Disorders	Pruritus, urticaria, rash
General Disorders and Administration Site Conditions	Infusion site reaction
	Pyrexia
Immune System Disorders	Anaphylactic reaction, other hypersensitivity reactions

Drug Interactions

None known.

USE IN SPECIFIC POPULATIONSPregnancy

Pregnancy Category C.

Animal reproduction studies have not been conducted with Kogenate FS. It is also not known whether Kogenate FS can cause fetal harm when administered to a pregnant woman or affect reproduction capacity. Kogenate FS should be used during pregnancy only if clinically needed.

Labor and Delivery

There is no information available on the effect of factor VIII replacement therapy on labor and delivery. Kogenate FS should be used only if clinically needed.

Nursing Mothers

It is not known whether this drug is excreted into human milk. Because many drugs are excreted into human milk, caution should be exercised if Kogenate FS is administered to nursing mothers. Kogenate FS should be given to nursing mothers only if clinically needed.

Pediatric Use

Safety and efficacy studies have been performed in previously untreated and minimally treated pediatric patients. Children in comparison to adults present higher factor VIII clearance values and thus lower recovery of factor VIII. This may be explained by differences in body composition7 and should be taken into account when dosing or following factor VIII levels in such a population. [See Clinical Pharmacology ( 12.3).] Routine prophylactic treatment in children ages 0-2.5 years with no pre-existing joint damage has been shown to reduce spontaneous joint bleeding and the risk of joint damage. This data can be extrapolated to ages >2.5-16 years for children who have no existing joint damage. [See Clinical Studies (14.3).]

Geriatric Use

Clinical studies with Kogenate FS did not include patients aged 65 and over. Dose selection for an elderly patient should be individualized.

Kogenate FS Description

Kogenate FS Antihemophilic Factor (Recombinant) is a coagulation factor VIII produced by recombinant DNA technology. It is produced by Baby Hamster Kidney (BHK) cells into which the human factor VIII gene has been introduced.8 The cell culture medium contains Human Plasma Protein Solution (HPPS) and recombinant insulin, but does not contain any proteins derived from animal sources. Kogenate FS is a purified glycoprotein consisting of multiple peptides including an 80 kD and various extensions of the 90 kD subunit. It has the same biological activity as factor VIII derived from human plasma. No human or animal proteins, such as albumin, are added during the purification and formulation processes of Kogenate FS.

The purification process includes a solvent/detergent virus inactivation step in addition to the use of the purification methods of ion exchange chromatography, monoclonal antibody immunoaffinity chromatography, along with other chromatographic steps designed to purify recombinant factor VIII and remove contaminating substances.

Additionally, the manufacturing process was investigated for its capacity to decrease the infectivity of an experimental agent of transmissible spongiform encephalopathy (TSE), considered as a model for the vCJD and CJD agents.9-21 Several of the individual production and raw material preparation steps in the Kogenate FS manufacturing process have been shown to decrease TSE infectivity of that experimental model agent. TSE reduction steps include the Fraction II+III separation step for HPPS (6.0 log10) and an anion exchange chromatography step (3.6 log10).

Kogenate FS is formulated with the following as stabilizers [see Table 7] in the final container and is then lyophilized. The final product is a sterile, nonpyrogenic, preservative-free, powder preparation for intravenous (IV) injection. Intravenous administration of sucrose contained in Kogenate FS will not affect blood glucose levels.

Table 7 Stabilizers Contained in Kogenate FS Final Container
Stabilizer	250 IU, 500 IU, 1000 IU	2000 IU, 3000 IU
Sucrose	0.9–1.3%	0.9–1.2%
Glycine	21–25 mg/mL	20–24 mg/mL
Histidine	18–23 mmol/L	17–22 mmol/L

 The following inactive ingredients/excipients are also contained in the final product:

Table 8 Inactive Ingredients/Excipients
Inactive Ingredient/Excipient	250 IU, 500 IU, 1000 IU	2000 IU, 3000 IU
Sodium	27–36 mEq/L	26–34 mEq/L
Calcium	2.0–3.0 mmol/L	1.9–2.9 mmol/L
Chloride	32–40 mEq/L	31–38 mEq/L
Polysorbate 80	64–96 µg/mL	64–96 µg/mL
Sucrose	28 mg/vial	52 mg/vial
Imidazole, tri-n-butyl phosphate, and copper	Trace amounts	Trace amounts

 Each vial of Kogenate FS contains the labeled amount of recombinant factor VIII in international units (IU). One IU, as defined by the World Health Organization standard for blood coagulation factor VIII, human, is approximately equal to the level of factor VIII activity found in 1 mL of fresh pooled human plasma.

Kogenate FS - Clinical PharmacologyMechanism of Action

Kogenate FS temporarily replaces the missing clotting factor VIII that is needed for effective hemostasis.

Pharmacodynamics

The aPTT is prolonged in patients with hemophilia. Determination of activated partial thromboplastin time (aPTT) is a conventional in vitro assay for biological activity of factor VIII. Treatment with Kogenate FS normalizes the aPTT over the effective dosing period.

Pharmacokinetics

The pharmacokinetic properties of Kogenate FS were investigated in two separate studies in previously treated patients, adults and children.

Pharmacokinetic studies with Kogenate FS were conducted in 20 PTPs (ages 12 to 33 years) with severe hemophilia A in North America. The pharmacokinetic parameters for Kogenate FS were measured in a randomized, crossover clinical trial with the predecessor KOGENATE product with a single dose administration of 50 IU/kg. After 24 weeks, the same dose of Kogenate FS was administered to the same patients. The recovery and half-life data for Kogenate FS were unchanged after 24 weeks of continued treatment with sustained efficacy and no evidence of factor VIII inhibition. [See Table 9.]

Table 9 Pharmacokinetic Parameters for Kogenate FS Compared to KOGENATE
Parameter	Kogenate FS		KOGENATE
	Initial PK Mean (±SD)	PK at week 24 Mean (±SD)	Reference Mean (±SD)
AUC (IU • h/dL)	1588.05 ± 344.32	1487.08 ± 381.73	1879.02 ± 412.32
Cmax (IU/dL)	114.95 ± 20.19	109.42 ± 20.09	127.40 ± 33.21
Half-life (hr)	13.74 ± 1.82	14.60 ± 4.38	14.07 ± 2.62
In Vivo Recovery (IU/dL / IU/kg)	2.20 ± 0.34	2.11 ± 0.37	2.43 ± 0.60

 The pharmacokinetics of Kogenate FS were investigated in pediatric PTPs (4.4-18.1 years of age, average age 12).7 The pharmacokinetic parameters in children compared to adults show differences in higher clearance, lower incremental in vivo factor VIII recovery and a shorter factor VIII half-life. This might be explained by differences in body composition such as body surface area and plasma volume. The pharmacokinetic parameters are depicted in Table 10.

Table 10 Pharmacokinetic Parameters for Kogenate FS in Children
Parameter	Mean (range)
AUC (IU • h/dL)	1320.0
Clearance (mL/h•kg)	4.1
Half-life (hr)	10.7 (7.8–15.3)
In Vivo Recovery (IU/dL / IU/kg)	1.9 (1.25–2.76)

 

Nonclinical Toxicology

Preclinical studies evaluating Kogenate FS in hemophilia A with mice, rats, rabbits, and dogs demonstrated safe and effective restoration of hemostasis. Doses several fold higher than the recommended clinical dose (related to body weight) did not demonstrate any acute or subacute toxic effect for Kogenate FS in laboratory animals.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies have been conducted with Kogenate FS to assess its mutagenic or carcinogenic potential and impairment of fertility. Kogenate FS has been shown to be comparable to the predecessor product with respect to its biochemical and physiochemical properties, as well as its non-clinical in vivo pharmacology and toxicology. By inference, the predecessor product and Kogenate FS would be expected to have equivalent mutagenic and carcinogenic potential.

The predecessor product did not demonstrate reverse mutation or chromosomal aberrations at doses substantially greater than the maximum expected clinical dose. In vivo evaluation with the predecessor product in animals using doses ranging between 10 and 40 times the expected clinical maximum also indicated that the predecessor product did not possess a mutagenic potential. Long-term investigations of carcinogenic potential in animals have not been performed due to the immune response to heterologous proteins in all non-human mammalian species.

Clinical StudiesPreviously Treated Patients

A total of 73 patients with severe (≤ 2% FVIII) hemophilia A, ages 12–59, who had been previously treated with other recombinant or with plasma-derived AHF products, were treated up to 54-months in open label studies with Kogenate FS in Europe and North America. A total of 5,684 bleeding episodes were treated during the studies. Patients could be treated on demand or on prophylaxis. Regularly scheduled prophylaxis treatment represented 76% of all infusions (treatment regimens of 2-3 infusions per week). [See Table 11.]

Table 11 Previously Treated Patients (PTPs) Clinical Trial Results
Clinical Parameters	Results
No. of Infusions of Kogenate FS Administered	24,924
No. of IU Administered	45 million IU
No. of Bleeds Treated with Kogenate FS	5,684
Percentage of Bleeds Treated with One or Two Infusions of Kogenate FS	one infusion: 79.7%, two infusions: 13.0% total: 92.7%
Mean Kogenate FS Dose per Treatment Infusion (in Europe and North America, Respectively)	Approximately 32.5 and 29.6 IU/kg per treatment infusion

 A total of 31 patients received Kogenate FS for 43 surgical procedures during the PTP studies. There were both minor and major surgery types, 27 and 16 respectively. The surgeon or treating physician assigned a rating to the hemostatic outcome according to 4 categories; “excellent”, “good,” “moderate,” or “none.” Hemostasis was rated as satisfactory (“excellent” or “good”) in all cases. [See Table 13.]

Previously Untreated and Minimally Treated Patients

Kogenate FS has been used in the treatment of bleeding episodes in pediatric previously untreated patients (PUPs) and minimally treated patients (MTPs) with severe (< 2% FVIII) hemophilia A. There were 37 PUPs and 24 MTPs (defined as having equal to or less than 4 exposure days) treated with a total of 9,419 infusions of Kogenate FS for a follow up duration up to 3.1 years. A total of 1047 bleeding episodes were treated.

Table 12 Previously Untreated and Minimally Treated Patients (PUPs and MTPs) Clinical Trial Results
Clinical Parameters	Results
No. of Infusions of Kogenate FS Administered	9,419
No. of Exposure Days to Kogenate FS (median)	115 exposure days
No. of IU Administered	7.5 million IU
No. of Bleeds Treated with Kogenate FS	1,047
Percentage of Bleeds Treated with One or Two Infusions of Kogenate FS	one infusion 73.1% two infusions 15.0% total: 88.1%

 A total of 29 surgical procedures were performed in 23 patients during the PUPs and MTPs study. There were both minor and major surgery types, 23 and 6 respectively. The surgeon or treating physician assigned a rating to the hemostatic outcome according to 4 categories; “excellent,” “good,” “moderate,” or “none.” Hemostasis was rated as satisfactory (“excellent” or “good”) in all cases. [See Table 13.]

Table 13 Surgical Procedures Performed During PTPs and PUPs/MTPs Clinical Trials
Type of Surgery	PTPs (N=31)		PUPs/MTPs (N=23)
	No. of Surgical Events	Outcome “Good” or “Excellent”	No. of Surgical Events	Outcome “Good” or “Excellent”
Minor Surgery (i.e., tooth extractions, catheter implantations, liver biopsies)	24	100%	21	100%
Major Surgery (i.e., joint replacements, craniotomies, gastrointestinal resection)	16	100%	6	100%
Total	43		29

Pediatric Prophylaxis and Joint Damage Risk Reduction  

A total of 65 boys less than 30 months of age with severe hemophilia A (FVIII level ≤ 2 IU/dL) and with ≤ 2 bleeds into each index joint and normal baseline joint imaging, were observed for up to 5.5 years in a multicenter, open-label, prospective, randomized, controlled clinical study.5 Patients received either 25 IU/kg every other day (primary prophylaxis; n=32) or at least 3 doses totaling a minimum of 80 IU/kg at the time of a bleeding episode (enhanced episodic; n=33). Joint damage was evaluated by magnetic resonance imaging (MRI) or radiography, as well as the frequency of bleeding episodes. Joint damage detected by MRI or radiography in the ankles, knees, and elbows (i.e., index joints) was statistically significantly lower (p=0.002) for subjects receiving prophylactic therapy (7%) than for subjects receiving episodic therapy (42%). This corresponds to a 6.29-fold relative risk of joint damage for subjects treated with enhanced episodic therapy compared to prophylaxis. The mean rate of index joint hemorrhages for subjects on episodic therapy was 4.89 bleeds per year, versus 0.63 bleeds per year observed in the prophylaxis arm. Three of 33 (9.1%) of subjects in the episodic arm experienced recurrent life threatening bleeds (intracranial, gastrointestinal) compared to no subjects in the prophylaxis arm. On a per joint basis, joints in the regular prophylaxis arm were 8-fold more likely to remain damage-free than those in the episodic arm. Joint damage was most frequently observed in ankle joints and was detected at higher rates by MRI than by radiography. Ankles were also the index joint that demonstrated the highest frequency of bleeding events in this study (left ankle, mean 2.7 hemorrhages; right ankle, mean 2.6 hemorrhages).

As shown in Table 14 below, the incidence of joint damage was statistically significantly lower in the prophylactic group as compared to the episodic treatment group when assessed by MRI, or either MRI or radiography, using predefined criteria (described below) for establishing joint damage. However, there was no statistically significant difference between the two groups when joint damage was assessed by radiography alone.

To evaluate joint damage, MRIs were scored using a scale developed by Nuss et al. ,22 and X-rays were scored using the method of Pettersson et al.23 Both scales have been validated in various clinical trials and are routinely used for joint damage evaluation in hemophiliacs. Joint damage was defined as bone and/or cartilage damage including subchondral cysts, erosions and cartilage loss with narrowing of joint space. This corresponded to a total MRI score of ≥7 or an X-ray score of ≥ 1 in any of the following categories: subchondral cysts, erosions of joint surfaces or narrowing of joint spaces. Images were read separately by two independent radiologists centrally. Any discrepant reading was read by an independent third radiologist who was not aware of the initial reading results. The concordant reading of two out of three readers was used for analysis purposes.

Table 14 Subjects with Joint Damage (Subjects with Available Baseline and Endpoint Data)
Endpoint Assessment	Prophylaxis		Episodic Therapy		p-value
	Incidence (%)	Relative Risk (95% CI)	Incidence (%)	Relative Risk (95% CI)
MRI	2/27 (7%)	0.17 (0.04, 0.67)	13/29 (45%)	6.05 (1.50, 24.38)	0.002
Radiography	1/28 (4%)	0.19 (0.02, 1.55)	5/27 (19%)	5.19 (0.65, 41.54)	0.101
MRI or Radiography	2/30 (7%)	0.16 (0.04, 0.65)	13/31 (42%)	6.29 (1.55, 25.55)	0.002

Relative Risk is the risk of damage to one or more index joints on the given therapy as compared to the other therapy.

P-value is from the 2-sided Fisher Exact Test comparing the incidence of joint damage between treatment groups.

As shown in Table 15 below, the assessment of endpoints in all randomized subjects assuming that those without complete baseline and endpoint data are treatment failures (intention-to-treat analysis). The incidence of joint damage was statistically significantly lower in the prophylactic group as compared to the episodic treatment group, with similar p-values, when assessed by MRI, or either MRI or radiography.

Table 15 Subjects with Joint Damage (All Randomized Subjects Assuming Subjects without Complete Baseline and Endpoint Data as Treatment Failures)
Endpoint Assessment	Prophylaxis (n=32)		Episodic Therapy (n=33)		p-value
	Incidence (%)	Relative Risk (95% CI)	Incidence (%)	Relative Risk (95% CI)
MRI	7 (22%)	0.42 (0.20, 0.88)	17 (52%)	2.35 (1.13, 4.90)	0.020
Radiography	5 (16%)	0.47 (0.18, 1.20)	11 (33%)	2.13 (0.83, 5.45)	0.150
MRI or Radiography	8 (25%)	0.43 (0.22, 0.85)	19 (58%)	2.30 (1.18, 4.49)	0.012

Relative Risk is the risk of damage to one or more index joints on the given therapy as compared to the other therapy.

P-value is from the 2-sided Fisher Exact Test comparing the incidence of joint damage between treatment groups.

REFERENCES

1. White GC, Rosendaal F, Aledort LM, Lusher JM, Rothschild C, Ingerslev J, for the Factor VIII and Factor IX Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definitions in hemophilia. Thromb Haemost 85:560-75, 2001.

2. Abildgaard CF, Simone JV, Corrigan JJ, et al: Treatment of hemophilia with glycine-precipitated Factor VIII. N Engl J Med 275(9):471–5, 1966.

3. Schwartz RS, Abildgaard CF, Aledort LM, et al: Human recombinant DNA-derived antihemophilic factor (factor VIII) in the treatment of hemophilia A. Recombinant Factor VIII Study Group. N Engl J Med323(26):1800-5, 1990.

4. White GC 2nd, Courter S, Bray GL, et al: A multicenter study of recombinant factor VIII (Recombinate) in previously treated patients with hemophilia A. The Recombinate Previously Treated Patient Study Group.Thromb Haemost 77(4):660-667, 1997.

5. Manco-Johnson MJ, Abshire TC, Shapiro AD, Riske B, Hacker MR, Kilcoyne R, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med2007;357(6):535-44.

6. Kasper CK: Complications of hemophilia A treatment: factor VIII inhibitors. Ann NY Acad Sci 614:97–105, 1991.

7. Barnes C, Lillicrap D, Pazmino-Canizares J, et al: Pharmacokinetics of recombinant factor VIII (Kogenate-FS®) in children and causes of inter-patient pharmacokinetic variability. Haemophilia 12 (Suppl. 4): 40-49, 2006.

8. Lawn RM, Vehar GA: The molecular genetics of hemophilia. Sci Am 254(3):48–54, 1986.

9. Kimberlin RH, Walker CA: Characteristics of a short incubation model of scrapie in the golden hamster. J Gen Virol 34(2):295-304, 1977.

10. Kimberlin RH, Walker CA: Evidence that the transmission of one source of scrapie agent to hamsters involves separation of agent strains from a mixture. J Gen Virol 39(3):487-96, 1978.

11. Kimberlin RH, Walker CA: Pathogenesis of scrapie (strain 263K) in hamsters infected intracerebrally, intraperitoneally or intraocularly. J Gen Virol 67(2):255-63, 1986.

12. Prusiner SB, et al: Further purification and characterization of scrapie prions. Biochemistry 21(26):6942-50, 1982.

13. Kascsak RJ, et al: Mouse polyclonal and monoclonal antibody to scrapie-associated fibril proteins. J Virol 61(12):3688-93, 1987.

14. Rubenstein R, et al: Scrapie-infected spleens: analysis of infectivity, scrapie-associated fibrils, and protease-resistant proteins. J Infect Dis 164(1):29-35, 1991.

15. Taylor DM, Fernie K: Exposure to autoclaving or sodium hydroxide extends the dose-response curve of the 263K strain of scrapie agent in hamsters. J Gen Virol 77(4):811-13, 1996.

16. Stenland CJ, et al: Partitioning of human and sheep forms of the pathogenic prion protein during the purification of therapeutic proteins from human plasma. Transfusion 42(11):1497-500, 2002.

17. Lee DC, Miller JL, Petteway SR: Pathogen safety of manufacturing processes for biological products: special emphasis on KOGENATE® Bayer. Haemophilia 8(Suppl. 2):6-9, 2002.

18. Lee DC, Stenland CJ, Hartwell, RC, et al: Monitoring plasma processing steps with a sensitive Western blot assay for the detection of the prion protein. J Virol Methods 84(1):77-89, 2000.

19. Lee DC, Stenland CJ, Miller JL, et al: A direct relationship between the partitioning of the pathogenic prion protein and transmissible spongiform encephalopathy infectivity during the purification of plasma proteins. Transfusion 41(4):449-55, 2001.

20. Cai K, Miller JL, Stenland CJ, et al: Solvent-dependent precipitation of prion protein. Biochim Biophys Acta 1597(1):28-35, 2002.

21. Trejo SR, Hotta JA, Lebing W, et al: Evaluation of virus and prion reduction in a new intravenous immunoglobulin manufacturing process. Vox Sang 84(3):176-87, 2003.

22. Nuss R, Kilcoyne RF, Geraghty S, et al: MRI findings in haemophilic joints treated with radiosynoviorthesis with development of an MRI scale of joint damage. Haemophilia 6:162-169, 2000.

23. Pettersson H, Ahlberg A, Nilsson IM: A radiologic classification of hemophilia arthropathy. Clin Orthop Relat Res 149:153-159, 1980.

How Supplied/Storage and HandlingHow Supplied

Kogenate FS Antihemophilic Factor (Recombinant) with BIO-SET®, a needleless self-contained system, is supplied in the following single use glass vial sizes. A prefilled diluent syringe containing sterile water (meets USP chemistry requirements Sterile Water for Injection, except for pH) for reconstitution, an administration set, two alcohol swabs, one bandage, and one cotton pad are also provided.

NDC Number	Approximate FVIII Activity (IU)	Diluent (mL)
0026-3792-20	250	2.5
0026-3793-30	500	2.5
0026-3795-50	1000	2.5
0026-3796-60	2000	5.0
0026-3797-70	3000	5.0

 

Actual factor VIII activity in IU is stated on the label of each Kogenate FS Vial.

Storage and Handling

Product as Packaged for Sale:

· Store Kogenate FS at +2°C to +8°C (36°F to 46°F) for up to 30 months from the date of manufacture. Within this period, Kogenate FS may be stored for a period of up to 12 months at temperatures up to +25°C or 77°F, such as in home treatment situations.

· The starting date of room temperature storage should be clearly recorded on the unopened product carton. Once stored at room temperature, the product must not be returned to the refrigerator. The shelf-life then expires after the storage at room temperature, or the expiration date on the product vial, whichever is earlier.

· Do not use Kogenate FS after the expiration date indicated on the vial.

· Do not freeze.

· Protect from extreme exposure to light and store the lyophilized powder in the carton prior to use.

Product After Reconstitution:

· Administer Kogenate FS within 3 hours after reconstitution.

· It is recommended to use the administration set provided.

Patient Counseling Information

See Patient Product Information and Instructions for Use

Advise patients to report any adverse reactions or problems following Kogenate FS administration to their physician or healthcare provider.

· Allergic-type hypersensitivity reactions have been reported with Kogenate FS. Warn patients of the early signs of hypersensitivity reactions [including hives (rash with itching), generalized urticaria, tightness of the chest, wheezing, hypotension] and anaphylaxis. Advise patients to discontinue use of the product if these symptoms occur and seek immediate emergency treatment with resuscitative measures such as the administration of epinephrine and oxygen.

· In clinical studies with Kogenate FS, a 15% incidence of inhibitor development was observed in PUPs/MTPs and zero de-novo inhibitors were observed with the PTPs. Inhibitor formation may occur at any time in the treatment of a patient with hemophilia A. Advise patients to contact their physician or treatment center for further treatment and/or assessment, if they experience a lack of clinical response to factor VIII replacement therapy, as this may be a manifestation of an inhibitor.

· Advise patients to consult with their healthcare provider prior to travel. While traveling advise patients to bring an adequate supply of Kogenate FS based on their current regimen of treatment.

FDA-Approved Patient Labeling

Kogenate FS (kō-jen-ate)

Antihemophilic Factor (Recombinant)

Formulated with Sucrose

This leaflet summarizes important information about Kogenate FS with BIO-SET, a needleless self-contained reconstitution system. Please read it carefully before using this medicine. This information does not take the place of talking with your healthcare provider, and it does not include all of the important information about Kogenate FS. If you have any questions after reading this, ask your healthcare provider.

Do not attempt to self-infuse unless you have been taught how by your healthcare provider or hemophilia center.

What is Kogenate FS?

Kogenate FS is a medicine used to replace clotting factor (factor VIII or antihemophilic factor) that is missing in people with hemophilia A (also called “classic” hemophilia). Hemophilia A is an inherited bleeding disorder that prevents blood from clotting normally.

Kogenate FS is used to prevent and control bleeding in adults and children (0-16 years) with hemophilia A. Your healthcare provider may give you Kogenate FS when you have surgery. Kogenate FS can reduce the number of bleeding episodes when used regularly and reduce the risk of joint damage in children.

Kogenate FS is not used to treat von Willebrand's Disease.

Who should not use Kogenate FS?

You should not use Kogenate FS if you

· are allergic to rodents (like mice and hamsters).

· are allergic to any ingredients in Kogenate FS.

Tell your healthcare provider if you are pregnant or breast-feeding because Kogenate FS may not be right for you.

What should I tell my healthcare provider before I use Kogenate FS?

Tell your healthcare provider about all of your medical conditions.

Tell your healthcare provider and pharmacist about all of the medicines you take, including all prescription and non-prescription medicines, such as over-the-counter medicines, supplements, or herbal remedies.

Tell your healthcare provider if you have been told that you have inhibitors to factor VIII (because Kogenate FS may not work for you).

What are the possible side effects of Kogenate FS?

You could have an allergic reaction to Kogenate FS. Call your healthcare provider right away and stop treatment if you get

· rash or hives

· itching

· tightness of the chest or throat

· difficulty breathing

· light-headed, dizziness

· nausea

· decrease in blood pressure

Your body can also make antibodies, called “inhibitors,” against Kogenate FS, which may stop Kogenate FS from working properly. Consult with your healthcare provider to make sure you are carefully monitored with blood tests for the development of inhibitors to factor VIII.

Other common side effects of Kogenate FS are

· Local injection site reactions (pain, swelling, irritation at infusion site)

· Infections from implanted injection device

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

Finding veins for injections may be difficult in young children. When frequent injections are required your child's healthcare provider may propose to have a device surgically placed under the skin to facilitate access to the bloodstream. These devices may result in infections.

These are not all the possible side effects with Kogenate FS. You can ask your healthcare provider for information that is written for healthcare professionals.

How do I store Kogenate FS?

Do not freeze Kogenate FS.

Store Kogenate FS at +2°C to +8°C (36°F to 46°F) for up to 30 months from the date of manufacture. Within this period, Kogenate FS may be stored for a period of up to 12 months at temperatures up to +25°C or 77°F.

The starting date of room temperature storage should be clearly recorded on the unopened product carton. Once stored at room temperature, the product must not be returned to the refrigerator. The shelf-life then expires after the storage at room temperature, or the expiration date on the product vial, whichever is earlier. Store vials in their original carton and protect them from extreme exposure to light.

Reconstituted product (after mixing dry products with wet diluent) must be used within 3 hours and cannot be stored.

Throw away any unused Kogenate FS after the expiration date.

Do not use reconstituted Kogenate FS if it is not clear to slightly cloudy and colorless.

What else should I know about Kogenate FS and hemophilia A?

Medicines are sometimes prescribed for purposes other than those listed here. Do not use Kogenate FS for a condition for which it is not prescribed. Do not share Kogenate FS with other people, even if they have the same symptoms that you have.

This leaflet summarizes the most important information about Kogenate FS. If you would like more information, talk to your healthcare provider. You can ask your healthcare provider or pharmacist for information about Kogenate FS that was written for healthcare professionals.

Instructions for use

How should I take Kogenate FS?

Do not attempt to self-infuse unless you have been taught how by your healthcare provider or hemophilia center.

See the step-by-step instructions for reconstituting Kogenate FS with BIO-SET at the end of this leaflet and the specific infusion instruction leaflet provided.

You should always follow the specific instructions given by your healthcare provider. The steps listed below are general guidelines for using Kogenate FS. If you are unsure of the procedures, please call your healthcare provider before using.

Call your healthcare provider right away if bleeding is not controlled after using Kogenate FS.

Your healthcare provider will prescribe the dose that you should take.

Your healthcare provider may need to take blood tests from time to time.

Talk to your healthcare provider before traveling. You should plan to bring enough Kogenate FS for your treatment during this time.

Carefully handle Kogenate  FS. Dispose of all materials, including any leftover reconstituted Kogenate  FS product, in an appropriate container.

 

 

Reconstitution and use of Kogenate FS

Always work on a clean surface and wash your hands before performing the following procedures:

1. Prepare

A. Open

The easiest way to remove the cap from the vials is to move the top from side-to-side while pulling upward at the same time. This breaks the small plastic tabs that connect the cap to the top of the vial.

 

B. Remove Tip Cap

Remove the tamper-evident tip cap from the syringe. Separate the tip cap from the syringe by gently breaking it off. Hold the syringe in one hand while snapping off the tip cap with the other hand. Do not try to twist it off. Move it from side to side.

 

C. Connect Syringe

Connect the prefilled syringe to the powder vial by gently screwing it on clockwise on to the top of the vial until finger tight. Do not overtighten.

 

2. Activate

A. Activate (Spike the vial)

Place the vial on a solid, non-skid surface. Hold the vial firmly with one hand. With the other hand, place your thumb and forefinger on the fingerplate of the syringe and press down firmly on the fingerplate until it meets the top of the powder vial. This is the most critical step in the process. If the syringe is not pushed down firmly enough, the system will not be fully activated.

 

B. Connect Plunger Rod

Grasp the plunger rod at the top. Avoid contact with the rest of the plunger rod. Immediately connect it to the syringe by screwing the plunger rod clockwise into the rubber stopper.

 

C. Inject

Inject diluent into the vial by slowly pressing down the plunger rod. Pushing down the syringe too quickly may cause foaming in the vial. If this occurs, wait until the foam subsides before continuing.

 

D. Mix

Mix the diluent and powder by swirling gently and slowly. DO NOT SHAKE THE VIAL. Be sure the powder is completely dissolved before using.

 

3. Transfer

A. Transfer

Invert the vial, with the syringe still attached and smoothly draw all the solution into the syringe. Tilt the vial to the side and back to check that all remaining solution has been drawn into the large opening in the rubber stopper.

 

 

B. Disconnect

Disconnect the syringe from the empty vial by unscrewing it counterclockwise. DO NOT PULL THE SYRINGE FROM THE VIAL WITHOUT UNSCREWING IT FIRST.

 

C. Infuse

Attach the syringe to the butterfly set by screwing it in clockwise and follow the infusion instructions provided with Kogenate FS with BIO-SET.

 

Rate of administration

The entire dose of Kogenate  FS can usually be infused within 1 to 15 minutes. However, your healthcare provider will determine the rate of administration that is best for you.

Resources at Bayer available to the patient:

For Adverse Reaction Reporting contact:

Bayer Medical Communications 1-888-84-BAYER (1-888-842-2937)

Contact Bayer to receive more product information:

Kogenate FS Customer Service 1-888-606-3780

Bayer Reimbursement HELPline 1-800-288-8374

For more information, visit www.kogenatefs.com

Bayer HealthCare LLC Tarrytown, NY 10591 USA

U.S. License No. 8

(License Holder: Bayer Corporation)

Kogenate FS with BIO-SET Carton 250 IU

NDC 0026-3792-20

Kogenate FS

Antihemophilic

Factor

(Recombinant)

With BIO-SET

Formulated with

Sucrose

 

Kogenate FS with BIO-SET Carton 500 IU

NDC 0026-3793-30

Kogenate FS

Antihemophilic

Factor

(Recombinant)

With BIO-SET

Formulated with

Sucrose

 

Kogenate FS with BIO-SET Carton 1000 IU

NDC 0026-3795-50

Kogenate FS

Antihemophilic

Factor

(Recombinant)

With BIO-SET

Formulated with

Sucrose

 

Kogenate FS with BIO-SET Carton 2000 IU

NDC 0026-3796-60

Kogenate FS

Antihemophilic

Factor

(Recombinant)

With BIO-SET

Formulated with

Sucrose

 

Kogenate FS with BIO-SET Carton 3000 IU

NDC 0026-3797-70

Kogenate FS

Antihemophilic

Factor

(Recombinant)

With BIO-SET

Formulated with

Sucrose

 

Kogenate FS antihemophilic factor (recombinant) kit

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0026-3795

Packaging # Item Code Package Description   1 NDC:0026-3795-50 1 KIT (KIT) in 1 BOX

Quantity of Parts Part # Package Quantity Total Product Quantity     Part 1 1 VIAL, SINGLE-USE 2.5 mL     Part 2 1 SYRINGE 2.5 mL

Part 1 of 2 Kogenate FS antihemophilic factor (recombinant) injection, powder, lyophilized, for solution

Product Information Item Code (Source) NDC:0026-4795     Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ANTIHEMOPHILIC FACTOR, HUMAN RECOMBINANT (ANTIHEMOPHILIC FACTOR, HUMAN RECOMBINANT) ANTIHEMOPHILIC FACTOR, HUMAN RECOMBINANT 1000 [iU]  in 2.5 mL

Inactive Ingredients Ingredient Name Strength CALCIUM   CHLORIDE ION   COPPER   GLYCINE   HISTIDINE   POLYSORBATE 80   SODIUM POLYMETAPHOSPHATE   SUCROSE   TRIBUTYL PHOSPHATE

Packaging # Item Code Package Description   1 NDC:0026-4795-01 2.5 mL in 1 VIAL, SINGLE-USE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA103332 03/17/2011

Part 2 of 2 DILUENT water solution

Product Information         Route of Administration INTRAVENOUS DEA Schedule

Inactive Ingredients Ingredient Name Strength WATER

Packaging # Item Code Package Description   1   2.5 mL in 1 SYRINGE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA103332 03/17/2011

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA103332 03/17/2011

Kogenate FS antihemophilic factor (recombinant) kit

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0026-3793

Packaging # Item Code Package Description   1 NDC:0026-3793-30 1 KIT (KIT) in 1 BOX

Quantity of Parts Part # Package Quantity Total Product Quantity     Part 1 1 VIAL, SINGLE-USE 2.5 mL     Part 2 1 SYRINGE 2.5 mL

Part 1 of 2 Kogenate FS antihemophilic factor (recombinant) injection, powder, lyophilized, for solution

Product Information Item Code (Source) NDC:0026-4793     Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ANTIHEMOPHILIC FACTOR, HUMAN RECOMBINANT (ANTIHEMOPHILIC FACTOR, HUMAN RECOMBINANT) ANTIHEMOPHILIC FACTOR, HUMAN RECOMBINANT 500 [iU]  in 2.5 mL

Inactive Ingredients Ingredient Name Strength CALCIUM   CHLORIDE ION   COPPER   GLYCINE   HISTIDINE   POLYSORBATE 80   SODIUM POLYMETAPHOSPHATE   SUCROSE   TRIBUTYL PHOSPHATE

Packaging # Item Code Package Description   1 NDC:0026-4793-01 2.5 mL in 1 VIAL, SINGLE-USE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA103332 03/17/2011

Part 2 of 2 DILUENT water solution

Product Information         Route of Administration INTRAVENOUS DEA Schedule

Inactive Ingredients Ingredient Name Strength WATER

Packaging # Item Code Package Description   1   2.5 mL in 1 SYRINGE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA103332 03/17/2011

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA103332 03/17/2011

Kogenate FS antihemophilic factor (recombinant) kit

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0026-3792

Packaging # Item Code Package Description   1 NDC:0026-3792-20 1 KIT (KIT) in 1 BOX

Quantity of Parts Part # Package Quantity Total Product Quantity     Part 1 1 VIAL, SINGLE-USE 2.5 mL     Part 2 1 SYRINGE 2.5 mL

Part 1 of 2 Kogenate FS antihemphilic factor (recombinant) injection, powder, lyophilized, for solution

Product Information Item Code (Source) NDC:0026-4792     Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ANTIHEMOPHILIC FACTOR, HUMAN RECOMBINANT (ANTIHEMOPHILIC FACTOR, HUMAN RECOMBINANT) ANTIHEMOPHILIC FACTOR, HUMAN RECOMBINANT 250 [iU]  in 2.5 mL

Inactive Ingredients Ingredient Name Strength CALCIUM   CHLORIDE ION   COPPER   GLYCINE   HISTIDINE   POLYSORBATE 80   SODIUM POLYMETAPHOSPHATE   SUCROSE   TRIBUTYL PHOSPHATE

Packaging # Item Code Package Description   1 NDC:0026-4792-01 2.5 mL in 1 VIAL, SINGLE-USE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA103332 03/17/2011

Part 2 of 2 DILUENT water solution

Product Information         Route of Administration INTRAVENOUS DEA Schedule

Inactive Ingredients Ingredient Name Strength WATER

Packaging # Item Code Package Description   1   2.5 mL in 1 SYRINGE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA103332 03/17/2011

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA103332 03/17/2011

Kogenate FS antihemophilic factor (recombinant) kit

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0026-3796

Packaging # Item Code Package Description   1 NDC:0026-3796-60 1 KIT (KIT) in 1 BOX

Quantity of Parts Part # Package Quantity Total Product Quantity     Part 1 1 VIAL, SINGLE-USE 5 mL     Part 2 1 SYRINGE 5 mL

Part 1 of 2 Kogenate FS antihemophilic factor (recombinant) injection, powder, lyophilized, for solution

Product Information Item Code (Source) NDC:0026-4796     Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ANTIHEMOPHILIC FACTOR, HUMAN RECOMBINANT (ANTIHEMOPHILIC FACTOR, HUMAN RECOMBINANT) ANTIHEMOPHILIC FACTOR, HUMAN RECOMBINANT 2000 [iU]  in 5 mL

Inactive Ingredients Ingredient Name Strength CALCIUM   CHLORIDE ION   COPPER   GLYCINE   HISTIDINE   POLYSORBATE 80   SODIUM POLYMETAPHOSPHATE   SUCROSE   TRIBUTYL PHOSPHATE

Packaging # Item Code Package Description   1 NDC:0026-4796-01 5 mL in 1 VIAL, SINGLE-USE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA103332 03/17/2011

Part 2 of 2 DILUENT water solution

Product Information         Route of Administration INTRAVENOUS DEA Schedule

Inactive Ingredients Ingredient Name Strength WATER

Packaging # Item Code Package Description   1   5 mL in 1 SYRINGE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA103332 03/17/2011

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA103332 03/17/2011

Kogenate FS antihemophilic factor (recombinant) kit

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0026-3797

Packaging # Item Code Package Description   1 NDC:0026-3797-70 1 KIT (KIT) in 1 BOX

Quantity of Parts Part # Package Quantity Total Product Quantity     Part 1 1 VIAL, SINGLE-USE 5 mL     Part 2 1 SYRINGE 5 mL

Part 1 of 2 Kogenate FS antihemophilic factor (recombinant) injection, powder, lyophilized, for solution

Product Information Item Code (Source) NDC:0026-4797     Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ANTIHEMOPHILIC FACTOR, HUMAN RECOMBINANT (ANTIHEMOPHILIC FACTOR, HUMAN RECOMBINANT) ANTIHEMOPHILIC FACTOR, HUMAN RECOMBINANT 3000 [iU]  in 5 mL

Inactive Ingredients Ingredient Name Strength CALCIUM   CHLORIDE ION   COPPER   GLYCINE   HISTIDINE   POLYSORBATE 80   SODIUM POLYMETAPHOSPHATE   SUCROSE   TRIBUTYL PHOSPHATE

Packaging # Item Code Package Description   1 NDC:0026-4797-01 5 mL in 1 VIAL, SINGLE-USE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA103332 03/17/2011

Part 2 of 2 DILUENT water solution

Product Information         Route of Administration INTRAVENOUS DEA Schedule

Inactive Ingredients Ingredient Name Strength WATER

Packaging # Item Code Package Description   1   5 mL in 1 SYRINGE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA103332 03/17/2011

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA103332 03/17/2011

Labeler - Bayer HealthCare LLC (127769128)

Establishment
Name	Address	ID/FEI	Operations
Bayer HealthCare LLC		127769128	MANUFACTURE, API MANUFACTURE

 

Bayer HealthCare LLC