英文药名: Rebif(Interferon beta-1a Initiation Pack)

中文药名: 利比（干扰素β- 1a 注射剂）

生产厂家: Serono Inc.

药品名称

【药品名称】
通用名：重组人干扰素βla注射液
商品名：利比（Rebif）
英文名：Recombimant Human Interferon Beta Ia solution for Injection
本品的主要成分为：重组人干扰素βla。
赋形剂为：人血清白蛋白，甘露醇和醋酸钠。
【性状】
本品为无色澄清注射液，预装于带有不锈钢针头的玻璃注射器中。
规格

（1）8.8μg （2）22μg （3）44μg
病情简介

1. 什么是多发性硬化
多发性硬化(MS)是一种中枢神经系统脱髓鞘疾病，临床特点是病灶播散广泛病程中常有缓解复发的脑、脊髓和视神经神经损害。多发性硬化症是一种中枢神经系统的疾病，也就是说它的病变位于脑部或脊髓。我们的神经细胞有许多树枝状的神经纤维，这些纤维就像错纵复杂的电线一般，在我们的中枢神经系统中组织成绵密复杂的网络。大自然很巧妙的在我们神经纤维的外面包裹着一层叫「髓鞘」的物质，髓鞘不仅像电线的塑料皮一样让不同的电线不致短路，同时人体的髓鞘还可以加速我们神经讯号的传导。当这些髓鞘被破坏后，我们神经讯号的传导就会变慢甚至停止。多发性硬化症就是因为在中枢神经系统中产生大小不一的块状髓鞘脱失而产生症状。所谓「硬化」指的是这些髓鞘脱失的区域因为组织修复的过程中产生的疤痕组织而变硬。这些硬块可能会有好几个，随着时间的进展，新的硬块也可能出现，所以称作「多发性」。
2. 什么造成多发性硬化
虽然我们尚未厘清多发性硬化症确切的成因，但有几个环境因子以及遗传因子可能会促进自体免疫反应的发生。
*环境因素
研究者发现离赤道越远的地区，MS的发生率也跟着增加。即使是在美国，MS在北部比在南部来的常见。根据美国国家多发性硬化症协会的统计，MS的发生率在北纬37度以下是每十万人当中有57~78人。而在北纬37度以上的区域则是每十万人当中有110~140人—将近是北纬37度以下区域的两倍。 然而，为何MS会有此种分布型态，这仍是个待解之谜。有可能是环境当中的某些事件（例如：病毒）容易诱发自体免疫反应。
*遗传因素
一个个体是否容易受到MS的影响，遗传因子可能也是其中一项因素。假如家族中有一人罹患MS，则其它近亲罹患MS的机率也相对提高，例如：病患的子女或兄弟姊妹。MS病患其同卵双生的兄弟姊妹有33%的机率会发展出MS。然而，因为其发生机率并非100%，所以MS严格来说并不是一种遗传性疾病。
3. 神经系统发生了什么事?
多发性硬化症以几种方式影响脑部：
发炎反应的斑块可能会发生于脑部包裹轴突的髓鞘质和神经系统其它部分。发炎反应可能对髓鞘质造成损伤。
包裹轴突的髓鞘质可能会恶化或者丧失，称之为「脱髓鞘质」（demyelination）。
轴突可能因此而受损或是被破坏。
当髓鞘质被损坏，沿着轴突传递的电讯号遭到破坏。在发炎反应减缓之后，身体是有可能可以将受损的髓鞘质进行修复的。这个过程叫做「髓鞘质再生现象」（remyelination）。
4. 谁会得到多发性硬化症，症状为何？
病患通常在20~40岁时呈现出多发性硬化症的症状；女性罹患多发性硬化症的机率是男性的二~三倍。
一般的症状：
• 体感觉（触觉）发生问题像是手脚麻木或是感到刺痛
• 失去肌肉的强度或是灵敏度
• 走路，平衡，或协调出现问题
• 因为是神经发炎所引起的视觉问题
其它可能的症状：
• 膀胱以及肠子方面的问题
• 疼痛
• 疲劳
• 认知方面的问题(例如：思考，记忆)
• 忧郁
• 说话含糊不清
5. 怎么知道是不是得了多发性硬化？
多发性硬化症的某些早期症状可能也是其它疾病的征兆，因此它要做出正确的诊断可能很耗时。医师可能会使用磁振造影，腰椎穿刺以及诱发电位纪录来进行某些检验。
*磁振造影 (MRI)
MRI利用强力的磁场来取得脑部以及脊髓的影像。在MS病患中有70%~95%的病患，可以在MRI观察到发炎或受损的组织斑块。
*腰椎穿刺
腰椎穿刺是用来取得脑脊髓液样本的一种程序，脑脊髓液是一种环绕于脑部以及脊髓的液体。在脊髓的椎体之间插入长针，并且吸取一些脊髓液。多发性硬化症患者通常其脑脊髓液中的免疫细胞数目有上升的趋势。
*诱发电位
测量诱发电位包含了由头皮电极记录脑部的电位变化。闪光（视觉的诱发电位），声音（听觉诱发电位），或是皮肤的轻微振动（体感觉诱发电位）可以用来使大脑的电位活性同步化。 因为在多发性硬化症中包围着轴突的髓鞘质受损，神经细胞内的电子冲动比一般人的神经细胞来的小或慢。
6. 多发性硬化治疗的现状与未来
MS已基本被公认为是一种自身免疫性疾病，采用免疫干预治疗也成为了研究者们重点研究的治疗措施。现今MS的治疗措施研究的进展相当迅速，在临床应用中可选择的药物较之以往多了许多，而有些老药在用法上有了新的讨论。
药理毒理

药物治疗组：细胞因子，ATC编码：L03AB。 本品由人干扰素β天然氨基酸序列组成。它由哺乳动物（中国仓鼠卵巢）细胞产生，因而糖基化方式与天然蛋白相似。
本品对多发性硬化的明确作用机制仍在研究中。
本品的安全性和有效性已通过下述治疗方案在复发缓解型多发性硬化患者中进行了评价，即：剂量范围11-44μg（3MIU-12MIU），皮下注射，每周3次。按照批准的剂量，本品已被证明可以降低临床复发率（两年内降低约30%）及发病的严重程度。患者残疾进展（如定义的那样3个月后在EDSS方面至少有一个点的提高）的比例从39%（安慰剂组）降至30%（22μg治疗组）及27%（44μg治疗组）。经过4年的治疗，22μg治疗组患者平均恶化率降低22%。44μg治疗组患者平均恶化率降低29%（与用安慰剂治疗2年后分别以本品22μg或44μg治疗相比。
对继发进展型多发性硬化患者进行的3年临床试验表明，本品对残疾进展无显著疗效，但复发率降低约30%。如果将患者分为两组（入组前2年复发或未复方），本品对未复发的残疾患者无效，但对复发患者，研究结束时残疾进展的比例从70%（安慰组）降低到57%（22μg与44μg联合使用组）。若后一组患者出现这种结果，应给予谨慎的分析。
由于本品尚未在原发进展型多性硬化患者中进行研究，所以不得用于此类患者。
猴6个月大及大鼠3个月的毒理试验表明，本品除一过性发热外尚未发现其它明显毒性。
本品即无致突变性也不会导致基因断裂。尚未进行致癌研究。
在猴中进行的胚胎/胎儿毒性研究表明本品无生死毒性。基于其它干扰素a和β的研究，不能排除流产危险性增加的可能性。尚无干扰素βla对男性生育能力有作用的资料。
药代动力学

健康志愿者静脉给药后，干扰素βla血清水平以多指数方式与注射剂量呈比例迅速下降。初始半衰期大约数分钟，终末半期为数小时，可能存在一个深藏的房室。皮下或肌肉注射本品后，血清中的干扰素β保持低水平，但在注射后12-24小时仍可检出。皮下或肌肉注射本品的动力学与干扰素β相同。单剂量注射60μg，平均在注射后3小时达到最大峰浓度6-10IU/ml（以免疫测定法测得）。以同样剂量皮下注射，48小时重复一次，4次后出现中度蓄积（约2.5倍AUC）。药效学的变化与本品的给药有关，但不受给药途径的影响。单次注射后，2-5A合成酶的细胞内和血清活性以及β-2微球蛋白和新蝶呤的血清浓度在24小时内升高，之后2天内降低。肌肉注射和皮下注射所产生的效应完全不同。每48小时皮下给药一次，4次后产生持续增强的生物学效应，而未出现任务耐受迹象。
干扰素βla主要通过肝脏和肾脏代谢和排泄。
适应症

本品适用于患有多发性硬化症（MS）且在过去两年内至少有2次复发的患者。
对不处于复发期的继发进展型多民性硬化患者，其有效率还未得到证实。请参阅"药代动力学"部分。
用法用量

本品的推荐剂量为：皮下注射44μg（12MIU），每周3次。对专家认为不能耐受高剂量的患者，推荐剂量为：皮下注射：22μg（6MIU），每周3次。
初次治疗必须在有治疗此疾病经验的医生指导下进行。
首次使用本品时，为了产生快速减敏作用以减少不良反应，在最初2周内建议给药剂量为8.8μg（2.4MIU）（即44μg（12MIU）药品0.1ml或22μg（6MIU）药品0.2ml）；第3-4周，给予22μg（6MIU）（44μg（12MIU）药品0.25ml或全量22μg（6MIU））；从第5周起给予全量44μg（12MIU）。
至今为止，尚不清楚患者多长时间可治愈。治疗4年以上的安全性及有效性尚未得到证实。建议患者在开始治疗后的4年内至少每隔一年做一次检查。主治医生依个体情况决定长期治疗方案。
不良反应

a) 总体描述：
接受本品治疗的患者在开始治疗的第一个六个月中，有40%预计会出现典型的假流感样症状。大部分患者会有注射部位的反应，主要为轻微炎症及红斑。肝功的的实验室参数无症状升高及白细胞降低也常见。大多数观察到的干扰素βla的不良反应通常都很轻微且可逆，当剂量减少里反应良好。为避免严重或持续的不良反应，根据医生的意见可暂时减少本品的剂量或中断给药。
b) 常见的不良反应
下列不良反应报告根据发生的频率进行分类：
很常见 >1/10
常见 1/100-1/10
不常见 1/1000-1/100
罕见 1/10000-1/1000
很罕见 <1/10000
临床试验中不确定的不良反应：所列数据来自多发性硬化临床试验的数据库（安慰剂=824名患者；本品22μgTIW=398名患者；本品44μgTIW=727名患者），为六个月中观察到的不良反应发生率（大于安慰剂）。
注射部位的不适：
很常见：注射部位炎症及反应；
常见：注射部位疼痛；
不常见；注射部位坏死、脓肿及结块。
全身不适：
很常见：流感样症状，头痛；
常见：肌肉痛、关节痛、乏力、寒颤、发烧。肝、胆系统异常：
很常见：转氨酶无症状升高。
皮肤及四肢不适：
常见：瘙痒、皮疹、红斑状皮疹、斑丘疹。
红细胞及白细胞异常：
常见：嗜中性白血球减少、淋巴细胞减少、白血球减少、血小板减少、贫血。
内分泌异常：
不常见：甲状腺功能障碍（T3、T4升高，TSH降低）。
胃肠功能异常：
常见：腹泻、呕吐、恶心。
精神异常：
常见：忧郁、失眠。
上市后监控时确定的不良反应。
全身：
很罕见：过敏反应。
皮肤及四肢不适：
很罕见：血管神经性水肿、风疹、多形性红斑、多形性红斑样皮肤反应、脱发。
肝、胆系统异常：
罕见：肝炎（有或没有黄疸）。
中枢和周围神经系统：
很罕见：惊厥。
周围血管（心脏外）：
很罕见：血栓栓塞。
精神异常：
很罕见：自杀倾向。
c) 个体严重和/或经常发生的不良反应特性信息
本品与其它干扰素β一样，具有引起严重肝脏损害包括急性肝功能衰竭的潜在危险。罕有症状的肝功能障碍的机理不清。大多数严重肝脏损害在治疗的第一个六个月出现，特殊危因子还未确认。如果出现黄疸或其它功能障碍的临床症状则应停止本品治疗（见"注意事项"部分）。
d) 按药理学分类的不良反应
干扰素的使用也与食欲减退、头晕、焦虑、心律失常、血管舒张、心悸、月经过多及子宫出血有关。
在干扰素β的治疗期间可能出现自身抗体的形成增加。
禁忌

本品禁用于已知对天然或重组干扰素β、人血白蛋白或本品赋形剂过敏的患者。
同时也禁用于妊娠妇女（见"妊娠及哺乳期妇女用药"部分）、严重抑郁和/或有自杀想法的患者及有癫痫病史且经治疗未充分控制发作的患者。
注意事项

应告知患者与使用本品有关的最常见的不良反应，包括假流感综合症的症状（见"不良反应"部分）。
这些症状在治疗初期最明显，随着治疗的进行其发生率及严重程度均会降低。
有抑郁症状的患者慎用本品。已知多发性硬化患者中抑郁和自杀倾向的发生率较高且与干扰素的使用有关。使用本品的患者出现抑郁和/或自杀倾向症状时应立即通知主治医生，对这些患者应严密监测并给予适当的治疗，同时考虑停用本品（见"禁忌"及"不良反应"部分）。有癫痫发作史的患者应慎用本品。没有癫痫病史但在本品治疗过程中癫痫发作的患者，在重新开始βla干扰素治疗之前必须确定病因并给予适当的抗惊厥治疗。
心脏疾病，如心纹痛、充血性心力衰竭或心律失常的患者在开始本品治疗时若临床症状恶化，必须进行密切的监测。与本品治疗相关的假流感综合症状可能对心脏病患者造成困扰。
注射部位坏死在使用本品的患者中已有报道（见"不良反应"部分）。为减少注射部位发生坏死的危险，建议患者：
• 采用无菌注射技术
• 每次注射变换部位
对患者的自我注射过程特别是那些注射部位已发生反应的患者应进行定期检查。
如果发生皮肤损伤甚至伴有注射部位的肿胀和液体外渗，必须中止本品治疗直至皮肤操作痊愈。如果患者单处皮肤损伤的坏死面积不太大，则可继续治疗。
应告诉患者干扰素β可能会引起流产（见"妊娠及哺乳期妇女用药"及"药理毒理"部分）本品进行临床试验时，常见转氨酶无症状升高（尤其是ALT）并有1-3%的患者转氨酶高出正常值上限（ULN）的五倍。若ALT高于ULN5倍，应考虑降低本品剂量，当ALT恢复正常时再逐渐增加剂量。有肝病史、临床确诊的活动性肝炎、酒精滥用及ALT升高（>2.5倍ULN）的患者慎用本品。在治疗开始前，治疗的1、3、6个月及其后无临床症状的定期检查中应监测血清ALT水平。如果出现黄疸或肝功能障碍的其它临床症状应停止本品治疗。
本品与其它干扰素β一样，具有引起严重肝脏损害包括急性肝功能衰竭的潜在危险。罕有症状的肝功能障碍的机理不清。特殊危险因素还未确认。使用干扰素可引起化验结果的异常。因此，对多发性硬化患者除了通常要求进行监测的实验室参数之外，在使用本品时还建议进行肝酶监测、白细胞总数和分类以及血小板计数检查。
接受本品治疗的患者可能出现甲状腺功能异常或使甲状腺异常恶化。建议进行基础甲状腺功能检查，如结果异常，在治疗开始后的每6-12个月重复检查；若基础检查结果正常，除非出现甲状腺功能障碍的临床表现，否则不必进行常规检查（见"不良反应"部分）。
严重肾脏或肝脏功能损害的患者及严重骨髓抑制的患者使用本品时应谨慎并进行密切监测。
可能出现抗干扰素βla的血清中和抗体。出现这些抗体的精确发生率尚不肯定。临床资料表明，使用本品24-48个月后，约24%使用22μg（6MIU）剂量的患者及约13-14%使用44μg （12MIU）剂量的患者出现抗本品的血清抗体。这些抗体的出现已表明可降低本品（β-2微球蛋白和新蝶呤）的药效。尽管抗体产生的临床意义尚未完全阐明，但中和抗体的产生和临床有效性及MRI变量的降低有关。若患者对本品的治疗反应不足且产生中和抗体，其主治医生应重新评价继续使用本品的利益/风险比。
血清抗体测定的不同及抗体阳性定义的不同，限制了不同产品间抗原性的可比性。
对本品用于不能行走的多发性硬化患者的安全性及有效性仅有少量资料。
装于注射器中的溶液可直接使用。
任何未用的产品或废弃物应按当地要求处理。
妊娠及哺乳期妇女用药

本品不得用于妊娠或哺乳期妇女。
儿童用药

尚无本品用于16岁以下儿童多发性硬化的经验，因此本品不得用于这类患者。
药物相互作用

尚未进行本品与其它药物在人体中相互作用情况的研究。
对于干扰素在人和动物中降低肝脏细胞色素P-450依赖酶活性已有报道。当本品和治疗指数狭窄并在很大程度上依赖肝脏细胞色素P-450系统清除的药物（如抗癫痫药或某些类型的抗抑郁药）联合应用时须谨慎。
对本品与皮质类固醇或促肾上腺皮质激素的相互作用尚未进行过系统研究。临床研究表明，多发性硬化患者在复发期可使用本品和皮质类固醇或促肾上腺皮质激素治疗。
尚未在妊娠妇女中进行过本品的研究。在猴子中，使用其它大剂量干扰素可引起流产（见"药理毒理"部分）。这种作用在人类中不能排除。
接受本品治疗的育龄妇女必须采取适当的避孕措施。对打算妊娠或已妊娠患者应告诉她本品对胎儿可能造成的危害并中止本品治疗。
尚不清楚本品是否能够进入母乳。由于哺乳可能导致严重的不良反应，因此必须停止哺乳或中止本品治疗。
对驾驶或操作机械能力的影响

与使用本品有关的中枢神经系统的罕见不良反应可能影响患者驾驶或操作机械的能力（见"不良反应"部分）。
药物过量

迄今为止尚无药物过量的报道，如果出现药物过量，应住院观察并给予适当的支持性治疗。
贮藏

于原包装中存放于2-8℃，不可冷冻。若暂无冷藏条件，本品可置于25℃以下，但最多不超过30天。应置于儿童接触不到的地方。效期后不得使用。

包装规格：6个 x 8.8mcg 和 6个 x 22mcg (12个预充注射器)

REBIF (interferon beta-1a) kit
REBIF (interferon beta-1a) injection, solution
[EMD Serono, Inc.]
DESCRIPTION

Rebif® (interferon beta-1a) is a purified 166 amino acid glycoprotein with a molecular weight of approximately 22,500 daltons.  It is produced by recombinant DNA technology using genetically engineered Chinese Hamster Ovary cells into which the human interferon beta gene has been introduced.  The amino acid sequence of Rebif® is identical to that of natural fibroblast derived human interferon beta.  Natural interferon beta and interferon beta-1a (Rebif®)are glycosylated with each containing a single N-linked complex carbohydrate moiety.

Using a reference standard calibrated against the World Health Organization natural interferon beta standard (Second International Standard for Interferon, Human Fibroblast GB 23 902 531), Rebif® has a specific activity of approximately 270 million international units (MIU) of antiviral activity per mg of interferon beta-1a determined specifically by an in vitro cytopathic effect bioassay using WISH cells and Vesicular Stomatitis virus.  Rebif® 8.8 mcg, 22 mcg and 44 mcg contain approximately 2.4 MIU, 6 MIU or 12 MIU, respectively, of antiviral activity using this method.

Rebif® (interferon beta-1a) is formulated as a sterile solution in a prefilled syringe intended for subcutaneous (sc) injection.  Each 0.5 mL (0.5 cc) of Rebif® contains either 22 mcg or 44 mcg of interferon beta-1a, 2 or 4 mg albumin (human) USP, 27.3 mg mannitol USP, 0.4 mg sodium acetate, Water for Injection USP. Each 0.2 mL (0.2 cc) of Rebif® contains 8.8 mcg of interferon beta-1a, 0.8 mg albumin (human) USP, 10.9 mg mannitol USP, 0.16 mg sodium acetate, and Water for Injection USP.

CLINICAL PHARMACOLOGY

General

Interferons are a family of naturally occurring proteins that are produced by eukaryotic cells in response to viral infection and other biological inducers. Interferons possess immunomodulatory, antiviral and antiproliferative biological activities. They exert their biological effects by binding to specific receptors on the surface of cells.   Three major groups of interferons have been distinguished: alpha, beta, and gamma.  Interferons alpha and beta form the Type I interferons and interferon gamma is a Type II interferon.  Type I interferons have considerably overlapping but also distinct biological activities.  Interferon beta is produced naturally by various cell types including fibroblasts and macrophages. Binding of interferon beta to its receptors initiates a complex cascade of intracellular events that leads to the expression of numerous interferon-induced gene products and markers, including 2’, 5’-oligoadenylate synthetase, beta 2-microglobulin and neopterin, which may mediate some of the biological activities.  The specific interferon-induced proteins and mechanisms by which interferon beta-1a exerts its effects in multiple sclerosis have not been fully defined.

Pharmacokinetics

The pharmacokinetics of Rebif® (interferon beta-1a) in people with multiple sclerosis have not been evaluated. In healthy volunteer subjects, a single subcutaneous (sc) injection of 60 mcg of Rebif® (liquid formulation), resulted in a peak serum concentration (Cmax) of 5.1 ± 1.7 IU/mL (mean ± SD), with a median time of peak serum concentration (Tmax) of 16 hours.  The serum elimination half-life (t1/2) was 69 ± 37 hours, and the area under the serum concentration versus time curve (AUC) from zero to 96 hours was 294 ± 81 IU·h/mL.  Following every other day sc injections in healthy volunteer subjects, an increase in AUC of approximately 240% was observed, suggesting that accumulation of interferon beta-1a occurs after repeat administration.  Total clearance is approximately 33-55 L/hour. There have been no observed gender-related effects on pharmacokinetic parameters.  Pharmacokinetics of Rebif® in pediatric and geriatric patients or patients with renal or hepatic insufficiency have not been established.

Pharmacodynamics

Biological response markers (e.g., 2’,5’-OAS activity, neopterin and beta 2-microglobulin) are induced by interferon beta-1a following parenteral doses administered to healthy volunteer subjects and to patients with multiple sclerosis.  Following a single sc administration of 60 mcg of Rebif® intracellular 2’,5’-OAS activity peaked between 12 to 24 hours and beta-2-microglobulin and neopterin serum concentrations showed a maximum at approximately 24 to 48 hours.  All three markers remained elevated for up to four days. Administration of Rebif® 22 mcg three times per week (tiw) inhibited mitogen-induced release of pro-inflammatory cytokines (IFN-γ, IL-1, IL-6, TNF-α and TNF-β) by peripheral blood mononuclear cells that, on average,  was near double that observed with Rebif® administered once per week (qw) at either 22 or 66 mcg.

The relationships between serum interferon beta-1a levels and measurable pharmacodynamic activities to the mechanism(s) by which Rebif® exerts its effects in multiple sclerosis are unknown. No gender-related effects on pharmacodynamic parameters have been observed.

CLINICAL STUDIES

Two multicenter studies evaluated the safety and efficacy of Rebif® in patients with relapsing-remitting multiple sclerosis.

Study 1 was a randomized, double-blind, placebo controlled study in patients with multiple sclerosis for at least one year, Kurtzke Expanded Disability Status Scale (EDSS) scores ranging from 0 to 5, and at least 2 acute exacerbations in the previous 2 years.(1)  Patients with secondary progressive multiple sclerosis were excluded from the study.  Patients received sc injections of either placebo (n = 187), Rebif® 22 mcg (n = 189), or Rebif® 44 mcg  (n = 184) administered tiw for two years.   Doses of study agents were progressively increased to their target doses during the first 4 to 8 weeks for each patient in the study (see DOSAGE AND ADMINISTRATION).

The primary efficacy endpoint was the number of clinical exacerbations. Numerous secondary efficacy endpoints were also evaluated and included exacerbation-related parameters, effects of treatment on progression of disability and magnetic resonance imaging (MRI)-related parameters.  Progression of disability was defined as an increase in the EDSS score of at least 1 point sustained for at least 3 months.   Neurological examinations were completed every 3 months, during suspected exacerbations, and coincident with MRI scans.  All patients underwent proton density T2-weighted (PD/T2) MRI scans at baseline and every 6 months.  A subset of 198 patients underwent PD/T2 and T1-weighted gadolinium-enhanced (Gd)-MRI scans monthly for the first 9 months.  Of the 560 patients enrolled, 533 (95%) provided 2 years of data and 502 (90%) received 2 years of study agent.

Study results are shown in Table 1 and Figure 1.  Rebif® at doses of 22 mcg and 44 mcg administered sc tiw significantly reduced the number of exacerbations per patient as compared to placebo. Differences between the 22 mcg and 44 mcg groups were not significant (p >0.05).

The exact relationship between MRI findings and the clinical status of patients is unknown.  Changes in lesion area often do not correlate with changes in disability progression.  The prognostic significance of the MRI findings in these studies has not been evaluated.

Table 1: Clinical and MRI Endpoints from Study 1

	Placebo	22 mcg tiw		44 mcg tiw
	n = 187	n = 189		n = 184
* p<0.05 compared to placebo ** p<0.001 compared to placebo *** p<0.0001 compared to placebo
(1) Intent-to-treat analysis
(2) Poisson regression model adjusted for center and time on study
(3) Logistic regression adjusted for center. Patients lost to follow-up prior to an exacerbation were excluded from this analysis (n = 185, 183, and 184 for the placebo, 22 mcg tiw, and 44 mcg tiw groups, respectively)
(4) Cox proportional hazard model adjusted for center
(5) ANOVA on ranks adjusted for center. Patients with missing scans were excluded from this analysis
Exacerbation-related
Mean number of exacerbations per patient over 2 years1,2	2.56	1.82**		1.73***
(Percent reduction)		(29%)		(32%)
Percent (%) of patients exacerbation-free at 2 years3	15%	25%*		32%***
Median time to first exacerbation (months)1,4	4.5	7.6**		9.6***
MRI	n = 172	n = 171	n = 171
Median percent (%) change of MRI PD-T2 lesion area at 2 years5	11.0	-1.2***	-3.8***
Median number of active lesions per patient per scan (PD/T2; 6 monthly)5	2.25	0.75***	0.5***

The time to onset of progression in disability sustained for three months was significantly longer in patients treated with Rebif® than in placebo-treated patients.  The Kaplan-Meier estimates of the proportions of patients with sustained disability are depicted in Figure 1.

The safety and efficacy of treatment with Rebif® beyond 2 years have not been established.

Study 2 was a randomized, open-label, evaluator-blinded, active comparator study.(2)  Patients with relapsing-remitting multiple sclerosis with EDSS scores ranging from 0 to 5.5, and at least 2 exacerbations in the previous 2 years were eligible for inclusion.  Patients with secondary progressive multiple sclerosis were excluded from the study.  Patients were randomized to treatment with Rebif® 44 mcg tiw by sc injection (n=339) or Avonex® 30 mcg qw by intramuscular (im) injection (n=338).  Study duration was 48 weeks.

The primary efficacy endpoint was the proportion of patients who remained exacerbation-free at 24 weeks. The principal secondary endpoint was the mean number per patient per scan of combined unique active MRI lesions through 24 weeks, defined as any lesion that was T1 active or T2 active.  Neurological examinations were performed every three months by a neurologist blinded to treatment assignment.  Patient visits were conducted monthly, and mid-month telephone contacts were made to inquire about potential exacerbations.  If an exacerbation was suspected, the patient was evaluated with a neurological examination.  MRI scans were performed monthly and analyzed in a treatment–blinded manner.

Patients treated with Rebif® 44 mcg sc tiw were more likely to remain relapse-free at 24 and 48 weeks than were patients treated with Avonex® 30 mcg im qw (Table 2).  This study does not support any conclusion regarding effects on the accumulation of physical disability.

Table 2: Clinical and MRI Results from Study 2

	Rebif®	Avonex®	Absolute Difference	Risk of relapse on Rebif® relative to Avonex®
* p <0.001, and ** p = 0.009,  Rebif® compared to Avonex®
(1) Logistic regression model adjusted for treatment and center, intent to treat analysis
(2) Nonparametric ANCOVA model adjusted for treatment and center, with baseline combined unique lesions as the single covariate.
Relapses Proportion of patients relapse-free at 24 weeks1 Proportion of patients relapse-free at 48 weeks	N=339 75%* 62%**	N=338 63% 52%	12% (95% CI: 5%, 19%) 10% (95%CI: 2%, 17%)	0.68 (95% CI: 0.54, 0.86) 0.81 (95%CI: 0.68, 0.96)
MRI (through 24 weeks) Median of the mean number of combined unique MRI lesions per patient per scan2(25th, 75th percentiles)	N=325 0.17* (0.00, 0.67)	N=325 0.33 (0.00, 1.25)

The adverse reactions over 48 weeks were generally similar between the two treatment groups.  Exceptions included injection site disorders (83% of patients on Rebif® vs. 28% of patients on Avonex®), hepatic function disorders (18% on Rebif® vs. 10% on Avonex®), and leukopenia (6% on Rebif® vs. <1% on Avonex®), which were observed with greater frequency in the Rebif® group compared to the Avonex® group.

INDICATIONS AND USAGE

Rebif® (interferon beta-1a) is indicated for the treatment of patients with relapsing forms of multiple sclerosis to decrease the frequency of clinical exacerbations and delay the accumulation of physical disability.  Efficacy of Rebif® in chronic progressive multiple sclerosis has not been established.

CONTRAINDICATIONS

Rebif® (interferon beta-1a) is contraindicated in patients with a history of hypersensitivity to natural or recombinant interferon, human albumin, or any other component of the formulation.

WARNINGS

Depression and Suicide

Rebif® (interferon beta-1a) should be used with caution in patients with depression, a condition that is common in people with multiple sclerosis.  Depression, suicidal ideation, and suicide attempts have been reported to occur with increased frequency in patients receiving interferon compounds, including Rebif®. In addition, there have been postmarketing reports of suicide in patients treated with Rebif®.  Patients should be advised to report immediately any symptoms of depression and/or suicidal ideation to the prescribing physician.  If a patient develops depression, cessation of treatment with Rebif® should be considered.

Hepatic Injury

Severe liver injury, including some cases of  hepatic failure requiring liver transplantation, has been reported  rarely in patients taking Rebif®.  Symptoms of liver dysfunction began from one to six months following the initiation of Rebif®.  If jaundice or other symptoms of liver dysfunction appear, treatment with Rebif® should be discontinued immediately due to the potential for rapid progression to liver failure.

Asymptomatic elevation of hepatic transaminases (particularly SGPT) is common with interferon therapy (see ADVERSE REACTIONS).  Rebif® should be initiated with caution in patients with active liver disease, alcohol abuse, increased serum SGPT (> 2.5 times ULN), or a history of significant liver disease.  Also, the potential risk of Rebif® used in combination with known hepatotoxic products should be considered prior to Rebif® administration, or when adding new agents to the regimen of patients already on Rebif®.  Reduction of Rebif® dose should be considered if SGPT rises above 5 times the upper limit of normal.  The dose may be gradually re-escalated when enzyme levels have normalized.    (See PRECAUTIONS: Laboratory Tests and Drug Interactions; and DOSAGE AND ADMINISTRATION).

Anaphylaxis

Anaphylaxis has been reported as a rare complication of Rebif® use.  Other allergic reactions have included skin rash and urticaria, and have ranged from mild to severe without a clear relationship to dose or duration of exposure.  Several allergic reactions, some severe, have occurred after prolonged use.

Albumin (Human)

This product contains albumin, a derivative of human blood.  Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases.  A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote.  No cases of transmission of viral diseases or CJD have ever been identified for albumin.

PRECAUTIONS

General

Caution should be exercised when administering Rebif® to patients with pre-existing seizure disorders.  Seizures have been associated with the use of beta interferons including Rebif®.    Leukopenia and new or worsening thyroid abnormalities have developed in some patients treated with Rebif® (see ADVERSE REACTIONS).  Regular monitoring for these conditions is recommended (see PRECAUTIONS: Laboratory Tests).

Information for Patients

All patients should be instructed to read the Rebif® Medication Guide supplied to them.  Patients should be cautioned not to change the dosage or the schedule of administration without medical consultation.

Patients should be informed of the most common and the most severe adverse reactions associated with the use of Rebif® (see WARNINGS and ADVERSE REACTIONS).  Patients should be advised of the symptoms associated with these conditions, and to report them to their physician.

Female patients should be cautioned about the abortifacient potential of Rebif® (see PRECAUTIONS:Pregnancy).

Patients should be instructed in the use of aseptic technique when administering Rebif®.  Appropriate instruction for self-injection or injection by another person should be provided, including careful review of the Rebif® Medication Guide.  If a patient is to self-administer Rebif®, the physical and cognitive ability of that patient to self-administer and properly dispose of syringes should be assessed.  The initial injection should be performed under the supervision of an appropriately qualified health care professional. Patients should be advised of the importance of rotating sites of injection with each dose, to minimize the likelihood of severe injection site reactions or necrosis.  A puncture-resistant container for disposal of used needles and syringes should be supplied to the patient along with instructions for safe disposal of full containers.  Patients should be instructed in the technique and importance of proper syringe disposal and be cautioned against reuse of these items.

Laboratory Tests

In addition to those laboratory tests normally required for monitoring patients with multiple sclerosis, blood cell counts and liver function tests are recommended at regular intervals (1, 3, and 6 months) following introduction of Rebif® therapy and then periodically thereafter in the absence of clinical symptoms. Thyroid function tests are recommended every 6 months in patients with a history of thyroid dysfunction or as clinically indicated. Patients with myelosuppression may require more intensive monitoring of complete blood cell counts, with differential and platelet counts.

Drug Interactions

No formal drug interaction studies have been conducted with Rebif®.  Due to its potential to cause neutropenia and lymphopenia, proper monitoring of patients is required if Rebif® is given in combination with myelosuppressive agents.

Also, the potential for hepatic injury should be considered when Rebif® is used in combination with other products associated with hepatic injury, or when new agents are added to the regimen of patients already on Rebif® (see WARNINGS: Hepatic Injury).

Immunization

In a nonrandomized prospective clinical study, 86 multiple sclerosis (MS) patients on Rebif® 44 mcg tiw for at least 6 months and 77 patients not receiving interferon received influenza vaccination.  The proportion of patients achieving a positive antibody response (defined as a titer > 1:40 measured by a hemagglutination inhibition assay) was similar in the two groups (93% and 91%, respectively).  The exact relationship of antibody titers to vaccine efficacy was not studied and is not known in patients receiving Rebif®.  Therefore, while patients receiving Rebif® may receive concomitant vaccination, the overall effectiveness of such vaccination is unknown.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis:  No carcinogenicity data for Rebif® are available in animals or humans. 

Mutagenesis: Rebif® was not mutagenic when tested in the Ames bacterial test and in an in vitro cytogenetic assay in human lymphocytes in the presence and absence of metabolic activation.

Impairment of Fertility:  No studies have been conducted to evaluate the effects of Rebif® on fertility in humans. In studies in normally cycling female cynomolgus monkeys given daily sc injections of Rebif® for six months at doses of up to 9 times the recommended weekly human dose (based on body surface area), no effects were observed on either menstrual cycling or serum estradiol levels.  The validity of extrapolating doses used in animal studies to human doses is not established.  In male monkeys, the same doses of Rebif® had no demonstrable adverse effects on sperm count, motility, morphology, or function.

Pregnancy Category C

Rebif® treatment has been associated with significant increases in embryolethal or abortifacient effects in cynomolgus monkeys administered doses approximately 2 times the cumulative weekly human dose (based on either body weight or surface area) either during the period of organogenesis (gestation day 21-89) or later in pregnancy. There were no fetal malformations or other evidence of teratogenesis noted in these studies.  These effects are consistent with the abortifacient effects of other type I interferons.  There are no adequate and well-controlled studies of Rebif® in pregnant women.  However, in Studies 1 and 2, there were 2 spontaneous abortions observed and 5 fetuses carried to term among 7 women in the Rebif® groups. If a woman becomes pregnant or plans to become pregnant while taking Rebif®, she should be informed about the potential hazards to the fetus, and discontinuation of Rebif® should be considered.

Nursing Mothers

It is not known whether Rebif® is excreted in human milk.  Because many drugs are excreted in human milk, caution should be exercised when Rebif® is administered to a nursing woman.

Pediatric Use: The safety and effectiveness of Rebif® in pediatric patients have not been studied.

Geriatric Use: Clinical studies of Rebif® did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

ADVERSE REACTIONS

The most frequently reported serious adverse reactions with Rebif® were psychiatric disorders including depression and suicidal ideation or attempt (see WARNINGS:  Depression).  The incidence of depression of any severity in the Rebif®-treated groups and placebo-treated group was approximately 25%. 

The most commonly reported adverse reactions were injection site disorders, influenza-like symptoms (headache, fatigue, fever, rigors, chest pain, back pain, myalgia), abdominal pain, depression, elevation of liver enzymes and hematologic abnormalities.  The most frequently reported adverse reactions resulting in clinical intervention (e.g., discontinuation of Rebif®, adjustment in dosage, or the need for concomitant medication to treat an adverse reaction symptom) were injection site disorders, influenza-like symptoms, depression and elevation of liver enzymes (see WARNINGS).

In Study 1, 6 patients randomized to Rebif® 44 mcg tiw (3%), and 2 patients who received Rebif® 22 mcg tiw (1%) developed injection site necrosis during two years of therapy.    Rebif® was continued in 7 patients and interrupted briefly in one patient. There was one report of injection site necrosis in Study 2 during 48 weeks of Rebif® treatment.  All events resolved with conservative management.

The rates of adverse reactions and association with Rebif® in patients with relapsing-remitting multiple sclerosis are drawn from the placebo-controlled study (n = 560) and the active comparator-controlled study (n = 339).

The population encompassed an age range from 18 to 55 years.  Nearly three-fourths of the patients were female, and more than 90% were Caucasian, largely reflecting the general demographics of the population of patients with multiple sclerosis.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of Rebif® cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice.

Table 3 enumerates adverse events and laboratory abnormalities that occurred at an incidence that was at least 2% more in either Rebif®-treated group than was observed in the placebo group.

  Table 3.  Adverse Reactions and Laboratory Abnormalities in Study 1

Body System				Placebo tiw	Rebif® 22 mcg tiw	Rebif® 44 mcg tiw
			Preferred Term	(n=187)	(n=189)	(n=184)
The adverse reactions were generally similar in Studies 1 and 2, taking into account the disparity in study durations.
BODY AS A WHOLE
	Influenza-like symptoms			51%	56%	59%
	Headache			63%	65%	70%
	Fatigue			36%	33%	41%
	Fever			16%	25%	28%
	Rigors			5%	6%	13%
	Chest Pain			5%	6%	8%
	Malaise			1%	4%	5%
INJECTION SITE DISORDERS
	Injection Site Reaction			39%	89%	92%
	Injection Site Necrosis			0%	1%	3%
CENTRAL & PERIPH NERVOUS SYSTEM DISORDERS
	Hypertonia			5%	7%	6%
	Coordination Abnormal			2%	5%	4%
	Convulsions			2%	5%	4%
ENDOCRINE DISORDERS
	Thyroid Disorder			3%	4%	6%
GASTROINTESTINAL SYSTEM DISORDERS
	Abdominal Pain			17%	22%	20%
	Dry Mouth			1%	1%	5%
LIVER AND BILIARY SYSTEM DISORDERS
	SGPT Increased			4%	20%	27%
	SGOT Increased			4%	10%	17%
	Hepatic Function Abnormal			2%	4%	9%
	Bilirubinaemia			1%	3%	2%
MUSCULO-SKELETAL SYSTEM DISORDERS
	Myalgia			20%	25%	25%
	Back Pain			20%	23%	25%
	Skeletal Pain			10%	15%	10%
HEMATOLOGIC DISORDERS
	Leukopenia			14%	28%	36%
	Lymphadenopathy			8%	11%	12%
	Thrombocytopenia			2%	2%	8%
	Anemia			3%	3%	5%
PSYCHIATRIC DISORDERS
	Somnolence			1%	4%	5%
SKIN DISORDERS
	Rash Erythematous			3%	7%	5%
	Rash Maculo-Papular			2%	5%	4%
URINARY SYSTEM DISORDERS
	Micturition Frequency			4%	2%	7%
	Urinary Incontinence			2%	4%	2%
VISION DISORDERS
		Vision Abnormal		7%	7%	13%
		Xerophthalmia		0%	3%	1%

Postmarketing Experience

In addition to adverse events reported from clinical trials, the following events have been reported during postmarketing use of Rebif®.  Because these reactions were reported voluntarily from a population of uncertain size, the frequency or a causal relationship to Rebif can not be reliably determined.

Blood and Lymphatic System Disorders: Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS).

Eye Disorders:  Retinal vascular disorders (i.e. retinopathy, cotton wool spots or obstruction of retinal artery or vein).

Hepatobiliary Disorders:  Rare cases of severe liver dysfunction, including hepatic failure requiring liver transplantation (See WARNINGS: Hepatic Injury).

Nervous System:  Seizures (see PRECAUTIONS: General).  Transient neurological symptoms (i.e., hypoesthesia, muscle spasm, paresthesia, difficulty walking, musculoskeletal stiffness) that mimic MS exacerbations of limited duration, temporally related to the injections and most prominent at the initiation of therapy. In some cases, these symptoms were associated with flu-like syndrome.

Psychiatric Disorders:  suicide (see WARNINGS: Depression and Suicide).

Skin and Subcutaneous Tissue Disorders: Injection site abscesses, injecton site infections, including cellulitis and necrosis requiring debridement, systemic antibiotic treatment and/or grafting; erythema multiforme, and Stevens-Johnson syndrome.

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity.  In study 1, the presence of neutralizing antibodies (NAb) to Rebif® was determined by collecting and analyzing serum pre-study and at 6 month time intervals during the 2 years of the clinical trial.  Serum NAb were detected in 59/189 (31%) and 45/184 (24%) of Rebif®-treated patients at the 22 mcg and 44 mcg tiw doses, respectively, at one or more times during the study.  The clinical significance of the presence of NAb to Rebif® is unknown.

The data reflect the percentage of patients whose test results were considered positive for antibodies to Rebif® using an antiviral cytopathic effect assay, and are highly dependent on the sensitivity and specificity of the assay.  Additionally, the observed incidence of NAb positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications and underlying disease.  For these reasons, comparison of the incidence of antibodies to Rebif® with the incidence of antibodies to other products may be misleading.

Anaphylaxis and other allergic reactions have been observed with the use of Rebif® (see WARNINGS: Anaphylaxis).

DRUG ABUSE AND DEPENDENCE

There is no evidence that abuse or dependence occurs with Rebif® therapy.  However, the risk of dependence has not been systematically evaluated.

OVERDOSAGE

Safety of doses higher than 44 mcg sc tiw has not been adequately evaluated.  The maximum amount of Rebif® that can be safely administered has not been determined.

DOSAGE AND ADMINISTRATION

Dosages of Rebif® shown to be safe and effective are 22 mcg and 44 mcg injected subcutaneously three times per week.  Rebif® should be administered, if possible, at the same time (preferably in the late afternoon or evening) on the same three days (e.g., Monday, Wednesday, and Friday) at least 48 hours apart each week (see CLINICAL STUDIES).  Generally, patients should be started at 20% of the prescribed dose tiw and increased over a 4-week period to the targeted dose, either 22 mcg or 44 mcg tiw (see Table 4).  Following the administration of each dose, any residual product remaining in the syringe should be discarded in a safe and proper manner.

A Rebif® Titration Pack containing 6 doses of 8.8 mcg (0.2 mL) and 6 doses of 22 mcg (0.5 mL) is available for use during the titration period.

Table 4: Schedule for Patient Titration

	Recommended Titration (% of final dose)	Titration dose for Rebif®    (22 mcg	Titration dose for Rebif®     (44 mcg
Weeks 1-2	20 %	4.4 mcg	8.8 mcg
Weeks 3-4	50 %	11 mcg	22 mcg
Weeks 5+	100 %	22 mcg	44 mcg

Leukopenia or elevated liver function tests may necessitate dose reduction or discontinuation  of Rebif®  administration  until toxicity is resolved (see WARNINGS:Hepatic Injury, PRECAUTIONS: General and ADVERSE REACTIONS).

Rebif® is intended for use under the guidance and supervision of a physician.  It is recommended that physicians or qualified medical personnel train patients in the proper technique for self-administering subcutaneous injections using the prefilled syringe.  Patients should be advised to rotate sites for sc injections (see PRECAUTIONS: Information for Patients).  Concurrent use of analgesics and/or antipyretics may help ameliorate flu-like symptoms on treatment days.  Rebif® should be inspected visually for particulate matter and discoloration prior to administration. 

Stability and Storage

Rebif® should be stored refrigerated between 2-8°C (36-46°F).  DO NOT FREEZE.  If a refrigerator is not available, Rebif® may be stored at or below 25° C/77° F for up to 30 days and away from heat and light.

Do not use beyond the expiration date printed on cartons.  Rebif® contains no preservatives. Each syringe is intended for single use.  Unused portions should be discarded.

HOW SUPPLIED

Rebif® is supplied as a sterile, preservative-free solution packaged in graduated, ready to use in 0.2 mL or 0.5 mL prefilled syringes with 29-gauge, 0.5 inch needle for subcutaneous injection.  The following package presentations are available.

Rebif® (interferon beta -1a) Titration Pack, NDC 44087-8822-1

- Six Rebif® 8.8 mcg prefilled syringes and Six Rebif® 22 mcg prefilled syringe

Rebif® (interferon beta -1a) 22 mcg Prefilled syringe

- Twelve Rebif® 22 mcg prefilled syringes, NDC 44087-0022-3

Rebif® (interferon beta -1a) 44 mcg Prefilled syringe

- Twelve Rebif® 44 mcg prefilled syringes, NDC 44087-0044-3

RX only.

References

1. PRISMS Study Group.  Randomized double-blind placebo-controlled study of interferon
   β-1a in relapsing/remitting multiple sclerosis.  Lancet 1998; 352: 1498-1504.
2. Panitch H. Goodin DS, Francis G, et al. Randomized, comparative study of interferon β-1a treatment regimens in MS.  The EVIDENCE Trial. Neurology 2002 59:1496-1506.

Manufacturer: EMD Serono, Inc. Rockland, MA 02370 U.S. License # 1773

Co-Marketed by:

EMD Serono, Inc.

Rockland, MA 02370

Pfizer Inc.

New York, NY 10017

Revised:  September 2009

*Avonex® is a registered trademark of Biogen Idec, Inc.

N6700101G

Medication Guide

Medication Guide
Rebif® (Rē-bif)
Interferon beta-1a
(in-ter-feer-on beta-one-â)

Please read this leaflet carefully before you start to use Rebif® and each time your prescription is refilled since there may be new information.   The information in this medication guide does not take the place of regularly talking with your doctor or healthcare professional.

What is the most important information I should know about Rebif®?

Rebif® will not cure multiple sclerosis (MS) but it has been shown to decrease the number of flare-ups and slow the occurrence of some of the physical disability that is common in people with MS.  Rebif® can cause serious side effects, so before you start taking Rebif®, you should talk with your doctor about the possible benefits of Rebif® and its possible side effects to decide if Rebif® is right for you.  Potential serious side effects include:

• Depression.  Some patients treated with interferons, including Rebif®, have become seriously depressed (feeling sad).  Some patients have thought about killing themselves and a few have committed suicide.  Depression (a sinking of spirits or sadness) is not uncommon in people with multiple sclerosis.  However, if you are feeling noticeably sadder or helpless, or feel like hurting yourself or others, you should tell a family member or friend right away and call your doctor as soon as possible.  Your doctor may ask that you stop using Rebif®.  You should also tell your doctor if you have ever had any mental illness, including depression, and if you take any medications for depression.
• Liver problems.  Your liver may be affected by taking Rebif® and a few patients have developed severe liver injury.  Your healthcare provider may ask you to have regular blood tests to make sure that your liver is working properly.  If your skin or the whites of your eyes become yellow or if you are bruising easily you should call your doctor right away.
• Risk to pregnancy.  If you become pregnant while taking Rebif® you should stop using Rebif® immediately and call your doctor.  Rebif® may cause you to lose your baby (miscarry) or may cause harm to your unborn child.  You and your doctor will need to decide whether the potential benefit of taking Rebif® is greater than the risks are to your unborn child.
  
• Allergic reactions.  Some patients taking Rebif® have had severe allergic reactions leading to difficulty breathing, and loss of consciousness.  Allergic reactions can happen after your first dose or may not happen until after you have taken Rebif® many times.  Less severe allergic reactions such as itching, flushing or skin bumps can also happen at any time.  If you think you are having an allergic reaction, stop using Rebif® immediately and call your doctor.
• Injection site problems.  Rebif® may cause redness, pain or swelling at the place where an injection was given.  Some patients have developed skin infections or areas of severe skin damage (necrosis) requiring treatment by a doctor. If one of your injection sites becomes swollen and painful or the area looks infected and it doesn’t heal within a few days, you should call your doctor.

What is Rebif®?

Rebif® is a type of protein called beta interferon that occurs naturally in the body.  It is used to treat relapsing forms of multiple sclerosis.  It will not cure your MS but may decrease the number of flare-ups of the disease and slow the occurrence of some of the physical disability that is common in people with MS.  MS is a life-long disease that affects your nervous system by destroying the protective covering (myelin) that surrounds your nerve fibers.  The way Rebif® works in MS is not known.

Who should not take Rebif®?

Do not take Rebif® if you:

• have had an allergic reaction such as difficulty breathing, flushing or hives to another interferon beta or to human albumin.

If you have any of the following conditions or serious medical problems, you should tell your doctor before taking Rebif®:

• Depression (a sinking feeling or sadness), anxiety (feeling uneasy or fearful for no reason), or trouble sleeping
• Liver diseases
• Problems with your thyroid gland
• Blood problems such as bleeding or bruising easily and anemia (low red blood cells) or low white blood cells
• Epilepsy
• Are planning to become pregnant

Tell your doctor about all medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements.  Rebif® and other medicines may affect each other causing serious side effects.  Talk to your doctor before you take any new medicines.

How should I take Rebif®?

Rebif® is given by injection under the skin (subcutaneous injection) on the same three days a week (for example, Monday, Wednesday and Friday).  Your injections should be at least 48 hours apart so it is best to take them the same time each day.  Your doctor will tell you what dose of Rebif® to use, and may change the dose based on how your body responds.  You should not change the dose without talking with your doctor.

If you miss a dose, you should take your next dose as soon as you remember or are able to take it, then skip the following day.  Do not take Rebif® on two consecutive days.  You should return to your regular schedule the following week.  If you accidentally take more than your prescribed dose, or take it on two consecutive days, call your doctor right away.

You should always follow your doctor’s instructions and advice about how to take this medication.  If your doctor feels that you, or a family member or friend may give you the injections then you and/or the other person should be trained by your doctor or healthcare provider in how to give an injection.  Do not try to give yourself (or have another person give you) injections at home until you (or both of you) understand and are comfortable with how to prepare your dose and give the injections.

Always use a new, unopened, prefilled syringe of Rebif® for each injection.  Never reuse syringes.

It is important that you change your injection site each time Rebif® is injected.  This will lessen the chance of you having a serious skin reaction at the spot where you inject Rebif®.  You should always avoid injecting Rebif® into an area of skin that is sore, reddened, infected or otherwise damaged.

At the end of this leaflet there are detailed instructions on how to prepare and give an injection of Rebif®.  You should become familiar with these instructions and follow your doctor’s orders before injecting Rebif®.

What should I avoid while taking Rebif®?

• Pregnancy.  You should avoid becoming pregnant while taking Rebif® until you have talked with your doctor.  Rebif® can cause you to lose your baby (miscarry).
• Breast feeding.  You should talk to your doctor if you are breast feeding an infant.  It is not known if the interferon in Rebif® can be passed to an infant in mother’s milk, and it is not known whether the drug could harm the infant if it is passed to an infant.
• Rebif® and other medicines may affect each other causing serious side effects.  Talk to your doctor before you take any new medicines.

What are the possible side effects of Rebif®?

• Flu-like symptoms.  Most patients have flu-like symptoms (fever, chills, sweating, muscle aches and tiredness).  For many patients, these symptoms will lessen or go away over time.  You should talk to your doctor about whether you should take an over the counter medication for pain or fever reduction before or after taking your dose of Rebif®.
• Skin reactions.  Soreness, redness, pain, bruising or swelling may occur at the place of injection. (see: “What is the most important information I should know about Rebif®?”)
• Depression and anxiety.  Some patients taking interferons have become very depressed and or anxious.  There have been patients taking interferons who have had thoughts about killing themselves.  If you feel sad or hopeless you should tell a friend or family member right away and call your doctor immediately.  (see: “What is the most important information I should know about Rebif®?”)
• Liver problems.  Your liver function may be affected.  If you develop symptoms of changes in your liver, including yellowing of the skin and whites of the eyes and easy bruising, call your doctor immediately.  (see: “What is the most important information I should know about Rebif®?”)
• Blood problems.  You may have a drop in the levels of infection-fighting blood cells, red blood cells or cells that help to form blood clots.  If the drop in levels are severe, they can lessen your ability to fight infections, make you feel tired or sluggish or cause you to bruise or bleed easily.
• Thyroid problems.  Your thyroid function may change.  Symptoms of changes in the function of your thyroid include feeling cold or hot all the time, change in your weight (gain or loss) without a change in your diet or amount of exercise you are getting.
• Allergic reactions. Some patients have had hives, rash, skin bumps or itching while they were taking Rebif®.  Other patients have had more serious allergic reactions such as difficulty breathing, or feeling light-headed.  You should tell your doctor if you think you are having an allergic reaction.  (see: “What is the most important information I should know about Rebif®?”)

Whether you experience any of these side effects or not, you and your doctor should periodically talk about your general health.  Your doctor may want to monitor you more closely and ask you to have blood tests done more frequently.

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

Storage Conditions

Rebif® is packaged in prefilled syringes with needles already attached to the syringe.

Rebif® should be stored refrigerated between 2-8°C (36-46°F).  DO NOT FREEZE.  If a refrigerator is not available, Rebif® may be stored at or below 25°C/77°F for up to 30 days and away from heat and light.

General Information About Prescription Medicines

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.  This medication has been prescribed for your particular medical condition.  Do not use it for another condition or give this drug to anyone else.  If you have any questions you should speak with your doctor or health care professional.  You may also ask your doctor or pharmacist for a copy of the information provided to them with the product.

Keep this and all drugs out of the reach of children.

Instructions for Preparing and Giving Yourself an Injection of Rebif®

Before you begin, gather all of the supplies listed below:

• Rebif® prefilled syringe with 29 gauge needle. You may wish to remove your syringe from the refrigerator at least 30 minutes prior to use and let it adjust to room temperature so the liquid is not cold.  Do not heat or microwave a syringe.
• Alcohol swabs (wipes) or cotton balls and rubbing alcohol
• Small adhesive bandage strip (if desired)
• Puncture resistant safety container for disposal of used syringes
• Antibacterial soap
• An over-the-counter pain or fever reducing medication, if your doctor has recommended that you take this prior to, at the same time, or after you give yourself Rebif® to help minimize the fever, chills, sweating and muscle aches (flu-like symptoms) that may occur.

When first starting treatment with Rebif®, your doctor may prescribe either the 22 mcg or 44 mcg dose of Rebif®.     You should gradually increase the dose over 4 weeks, starting at 20% of the prescribed dose for the first 2 weeks, half-dose for the second 2 weeks (weeks 3 and 4), and then the full dose prescribed by your doctor.

A Rebif® Titration Pack containing 6 syringes with 8.8 mcg (0.2 mL) and 6 syringes with 22 mcg (0.5 mL) is available for use during the titration period.  The following table explains how to use the Rebif® Titration Pack during the first four weeks to gradually increase your dose to 22 or 44 mcg.

		Your Prescribed Dose
Week of Use	Syringe to Use	22 mcg	44 mcg
Weeks 1 and 2	8.8 mcg syringe	Use half of syringe	Use full syringe
Weeks 3 and 4	22 mcg syringe	Use half of syringe	Use full syringe
Weeks 5 and On	22 or 44 mcg syringe	Use full syringe depending on your prescribed dose: 22 or 44 mcg

Preparing for an injection:

• Check the expiration date; do not use if the medication is expired.  The expiration date is printed on the syringe, and carton.
• Be sure that the dose, either 8.8 mcg, 22 mcg or 44 mcg, described on the carton is the same as the dose prescribed by your doctor.
• Remove the Rebif® syringe from the plastic packaging.  Keep the needle capped.
• Examine the contents of the syringe carefully. The liquid should be clear to slightly yellow.  Do not use if the liquid is cloudy, discolored or contains particles.
• Choose the injection site.  The best sites for giving yourself an injection are those areas with a layer of fat between the skin and muscle, like your thigh, the outer surface of your upper arm, your stomach or buttocks.  Do not use the area near your navel or waistline.  If you are very thin, use only the thigh or outer surface of the arm for injection.  Use a different site each time you inject (thigh, hip, stomach or upper arm, see Figure below).  Do not inject Rebif® into an area of your body where the skin is irritated, reddened, bruised, infected or abnormal in any way.
• Keep a record of the date and location of each injection.
• Wash your hands thoroughly with antibacterial soap before preparing to inject the medication.
• Clean the injection site with an alcohol swab (wipe) or cotton ball with rubbing alcohol using a circular motion.  To avoid stinging, you should let your skin dry before you inject Rebif®.

Giving yourself an injection of Rebif®

• Remove the needle cap from the syringe needle.
• If your doctor has told you to use less than the full 0.5 mL dose, slowly push the plunger in until the amount of medication left in the syringe is the amount your doctor told you to use.
• Use your thumb and forefinger to pinch a pad of skin surrounding the cleaned injection site (see figure).  Hold the syringe like a pencil with your other hand. 
  
• While still pinching the skin, swiftly insert the needle like a dart at about a 90 degree angle (just under the skin) into the pad of tissue as shown.
  
• After the needle is in, remove the hand that you used to pinch your skin and inject the drug using a slow, steady push on the plunger until all the medication is injected and the syringe is empty.
  
• Withdraw the needle and apply gentle pressure to the injection site with a dry cotton ball or sterile gauze.  Applying a cold compress or ice pack to the injection site after injection may help reduce local skin reactions.
• Put a small adhesive bandage strip over the injection site, if desired.
• After 2 hours, check the injection site for redness, swelling, or tenderness.  If you have a skin reaction and it doesn’t clear up in a few days, contact your doctor or nurse.

Disposing of Needles and Syringes

• There are special state or local laws for properly disposing of used needles and syringes.  Your doctor or health care professional will instruct you on how to discard your used syringe and needle and may provide you with a puncture resistant syringe disposal container called a Sharps container.
• Always keep your disposal container out of the reach of children.
• DO NOT throw the needle and syringe in the household trash or recycle.

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

Manufactured by:
EMD Serono, Inc.
Rockland, MA 02370
U.S. License 1773

Co-Marketed by:
EMD Serono, Inc.