等待内容更新

使用说明

 

【药品名称】
通用名：重组人干扰素βla注射液
商品名；利比
英文商品名：Rebif
英文通用名：Recombimant Human Interferon Beta Ia solution for Injection

【成份】
        利比的主要成份为：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】
        利比为无色澄清注射液，预装于带有不锈钢针头的玻璃注射器中。

【药理毒理】
        药物治疗组：细胞因子，ATC编码：L03AB。
        干扰素（IFNs）是一组内源性的糖蛋白，具有免疫调节、抗病毒及抗增生作用。
        利比由人干扰素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。
利比对多发性硬化的明确作用机制仍在研究中。
        利比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，利比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年后分别以利比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，利比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），利比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。
        由于利比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，利比除一过性发热外尚未发现其它明显毒性。
        利比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/胎儿毒性研究表明利比无生死毒性。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。皮下或肌肉注射利比后，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。皮下或肌肉注射利比的动力学与干扰素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）。药效学的变化与利比的给药有关，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】
        利比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，其还未得到证实。请参阅"药代动力学"部分。

【用法用量】
        利比的推荐剂量为：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。
        首次使用利比时，为了产生减敏作用以减少不良反应，在初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：
        接受利比治疗的患者在开始治疗的个六个月中，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利比的剂量或中断给药。
        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；利比22μgTIW=398名患者；利比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：
         c) 个体严重和/或经常发生的不良反应特性信息
        利比与其它干扰素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利比治疗（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】
        利比禁用于已知对天然或重组干扰素β、人血白蛋白或利比赋形剂过敏的患者。
        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】
        应告知患者与使用利比有关的常见的不良反应，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利比。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。使用利比的患者出现抑郁和/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，同时考虑停用利比（见"禁忌"及"不良反应"部分）。有癫痫发作史的患者应慎用利比。没有癫痫病史但在利比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利比治疗时若临床症状恶化，必须进行密切的监测。与利比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利比的患者中已有报道（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，必须中止利比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）
        利比进行临床试验时，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，应考虑降低利比剂量，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）的患者慎用利比。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利比治疗。
        利比与其它干扰素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，在使用利比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。
        接受利比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利比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。出现这些抗体的发生率尚不肯定。临床资料表明，使用利比24-48个月后，约24%使用22μg（6MIU）剂量的患者及约13-14%使用44μ （12MIU）剂量的患者出现抗利比的血清抗体。这些抗体的出现已表明可降低利比（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。若患者对利比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利比的利益/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。
         对利比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】
        利比不得用于妊娠或哺乳期妇女。

【儿童用药】
        尚无利比用于16岁以下儿童多发性硬化的经验，因此利比不得用于这类患者。

【药物相互作用】
        尚未进行利比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。当利比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。
        对利比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利比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利比的研究。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。
        接受利比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利比对胎儿可能造成的危害并中止利比治疗。
        尚不清楚利比是否能够进入母乳。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利比治疗。

【对驾驶或操作机械能力的影响】
        与使用利比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）。

【药物过敏】
        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。

【规格】
        44ug(6MIU)

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

【包装】
        利比有三种包装规格：1、3、12支/盒。
        每支0.5ml装于带有不锈钢针头的1ml玻璃注射器中。

【有效期】
        24个月

【进口药品注册证号】
        注册证号S20130072 

【生产企业】
        Merck Serono S.p.A.
        默克雪兰诺公司意大利药厂

 

Rebif

Generic Name: interferon beta-1a
Dosage Form: injection, solution

 

 

 

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.

The recommended dose of Rebif is either 22 mcg or 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.

Generally, patients should be started at 20% of the prescribed dose three times per week and increased over a 4-week period to the targeted dose, either 22 mcg three times per week (see Table 1) or 44 mcg three times per week (see Table 2). Patients prescribed a targeted dose of 22 mcg three times per week should use the prefilled syringes for titration.

A 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 in both Rebif prefilled syringes and Rebif Rebidose autoinjectors.

Table 1: Titration Schedule for a 22 mcg Prescribed Dose*
Week of Use	Dose	Syringe to Use	Amount of syringe
* Use only prefilled syringes, not autoinjectors, to titrate to the 22 mcg Prescribed Dose
Week 1 Titration	4.4 mcg	8.8 mcg syringe	Use half of syringe
Week 2 Titration	4.4 mcg	8.8 mcg syringe	Use half of syringe
Week 3 Titration	11 mcg	22 mcg syringe	Use half of syringe
Week 4 Titration	11 mcg	22 mcg syringe	Use half of syringe
Week 5 and after	22 mcg	22 mcg syringe or autoinjector	Use full syringe or autoinjector
Table 2: Titration Schedule for a 44 mcg Prescribed Dose*
Week of Use	Dose	Syringe or Autoinjector to Use	Amount of syringe or autoinjector
* Prefilled syringes or autoinjectors can be used to titrate to the 44 mcg Prescribed Dose
Week 1 Titration	8.8 mcg	8.8 mcg syringe or autoinjector	Use full syringe or autoinjector
Week 2 Titration	8.8 mcg	8.8 mcg syringe or autoinjector	Use full syringe or autoinjector
Week 3 Titration	22 mcg	22 mcg syringe or autoinjector	Use full syringe or autoinjector
Week 4 Titration	22 mcg	22 mcg syringe or autoinjector	Use full syringe or autoinjector
Week 5 and after	44 mcg	44 mcg syringe or autoinjector	Use full syringe or autoinjector

Decreased peripheral blood counts or elevated liver function tests may necessitate dose reduction or discontinuation of Rebif administration until toxicity is resolved [see Warnings and Precautions (5.2, 5.5)and Adverse Reactions (6)].

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 or injection device approved for use with Rebif. Injection depth of the Rebif Rebidose autoinjector is fixed at 8 mm; the health care provider should determine the injection technique.

The initial injection should be performed under the supervision of an appropriately qualified health care provider.

Appropriate instruction for self-injection or injection by another person should be provided to the patient or their caregiver, including careful review of the Rebif Medication Guide and the Rebif Rebidose autoinjector Instructions for Use that accompanies the product. Users should demonstrate competency in all aspects of the injection prior to independent use. If a patient is to self-administer Rebif, the physical and cognitive ability of that patient to self-administer and properly dispose of prefilled syringes or the Rebif Rebidose autoinjectors should be assessed. Patients with severe neurological deficits should not self-administer injections without assistance from a trained caregiver.

Advise patients and caregivers to:

visually inspect Rebif for particulate matter and discoloration prior to administrationuse aseptic technique when administering Rebifrotate site of injection with each dose to minimize the likelihood of severe injection site reactions or necrosis [see Warnings and Precautions, (5.4)]use a puncture-resistant container for safe disposal of used needles, prefilled syringes and Rebif Rebidose autoinjectorsdo not re-use needles, syringes or Rebif Rebidose autoinjectors

Concurrent use of analgesics and/or antipyretics may help ameliorate flu-like symptoms associated with Rebif use on treatment days.

Injection: 8.8 mcg per 0.2 mL in a graduated, single-dose Rebif prefilled syringeInjection: 22 mcg per 0.5 mL in a graduated, single-dose Rebif prefilled syringeInjection: 44 mcg per 0.5 mL in a graduated, single-dose Rebif prefilled syringeInjection: 8.8 mcg per 0.2 mL in a single-dose prefilled Rebif Rebidose autoinjectorInjection: 22 mcg per 0.5 mL in a single-dose prefilled Rebif Rebidose autoinjectorInjection: 44 mcg per 0.5 mL in a single-dose prefilled Rebif Rebidose autoinjector

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

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.

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 (6.1)]. 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 Warnings and Precautions (5.8); and Dosage and Administration (2.1)].

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. Discontinue Rebif if anaphylaxis occurs.

In controlled clinical trials, injection site reactions occurred more frequently in Rebif-treated patients (92% in the 44 mcg group and 89% in the 22 mcg group) than in placebo-treated patients (39%) and at a higher frequency in Rebif treated patients (83%) than in AVONEX-treated patients (28%). Injection site necrosis also occurred more frequently in Rebif-treated patients (3% in the 44 mcg group and 1% in the 22 mcg group) than in placebo-treated patients (0) during the two years of therapy. All events resolved with conservative management.

Injection site reactions including injection site pain, erythema, edema, cellulitis, abscess, and necrosis have been reported in the postmarketing setting. Some occurred more than 2 years after initiation of Rebif. Necrosis occurred at single and at multiple injection sites. Some cases of injection site necrosis required treatment with intravenous antibiotics and surgical intervention (debridement and skin grafting).

Patient understanding and use of aseptic self-injection techniques and procedures should be periodically evaluated, particularly if injection site necrosis has occurred. Patients should be advised of the importance of rotating sites of injection with each dose and not reusing syringes. Patients should be advised against injecting an area which is inflamed, edematous, erythematous, ecchymotic, or has any other signs of infection. These signs should be reported to a healthcare professional immediately.

Decreased peripheral blood counts in all cell lines, including pancytopenia, have been reported in Rebif-treated patients. In controlled clinical trials, leukopenia occurred at a higher frequency in Rebif-treated patients (36% in 44 mcg group and 28% in 22 mcg group) than in placebo-treated patients (14%) and at a higher frequency in Rebif-treated patients (6%) compared to the AVONEX-treated patients (<1%). Thrombocytopenia and anemia occurred more frequently in 44 mcg Rebif-treated patients (8% and 5%, respectively) than in placebo-treated patients (2% and 3%, respectively). In a pooled analysis of 7 placebo controlled trials with Rebif doses of 22 mcg or 44 mcg, the rate of pancytopenia (in subjects with normal baseline values who developed laboratory values less than the lower limit of normal for all 3 hematology parameters simultaneously) was higher in the total Rebif group (5.5 per 1000 subject-year) than in the placebo group (1.2 per 1000 subject-year). Patients should be monitored for symptoms or signs of decreased blood counts. Monitoring of complete blood and differential white blood cell counts is also recommended [see Dosage and Administration (2.1) and Warnings and Precautions (5.8)].

Cases of thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, some fatal, have been reported with interferon beta products, including Rebif. Cases have been reported several weeks to years after starting interferon beta products. Discontinue Rebif if clinical symptoms and laboratory findings consistent with TMA occur, and manage as clinically indicated.

Caution should be exercised when administering Rebif to patients with pre-existing seizure disorders. Seizures have been temporally associated with the use of beta interferons, including Rebif, in clinical trials and in postmarketing reports.

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. Patients with myelosuppression may require more intensive monitoring of complete blood cell counts, with differential and platelet counts [see Dosage and Administration (2.1) and Warnings and Precautions (5.5)]. New or worsening thyroid abnormalities have developed in some patients treated with Rebif. Thyroid function tests are recommended every 6 months in patients with a history of thyroid dysfunction or as clinically indicated.

The following adverse reactions are discussed in more detail in the Warnings and Precautions section of the label:

Depression and Suicide [see Warnings and Precautions (5.1)]Hepatic Injury [see Warnings and Precautions (5.2)]Anaphylaxis and Other Allergic Reactions [see Warnings and Precautions (5.3)]Injection Site Reactions including Necrosis [see Warnings and Precautions (5.4)]Decreased Peripheral Blood Counts [see Warnings and Precautions (5.5)]Thrombotic Microangiopathy [see Warnings and Precautions (5.6) ]Seizures [see Warnings and Precautions (5.7)]Laboratory Tests [see Warnings and Precautions (5.8)]

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.

A total of 712 patients with relapsing-remitting multiple sclerosis (RRMS) in two controlled clinical trials took Rebif (22 mcg or 44 mcg given three times per week) [see Clinical Studies (14)]. Ages ranged 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.

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 were injection site disorders, influenza-like symptoms, depression, and elevation of liver enzymes [see Warnings and Precautions (5)].

 

 

Study 1 was a 2-year placebo-controlled study in RRMS patients treated with Rebif 22 mcg (n=189), 44 mcg (n=184), or placebo (n=187). Table 3 enumerates adverse reactions 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 (n=187)	Rebif 22 mcg tiw (n=189)	Rebif 44 mcg tiw (n=184)
Preferred Term	%	%	%
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
NERVOUS SYSTEM DISORDERS
Hypertonia	5	7	6
Coordination Abnormal	2	5	4
Convulsions	2	5	4
Somnolence	1	4	5
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
Bilirubinemia	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
SKIN DISORDERS
Rash Erythematous	3	7	5
Rash Maculo-Papular	2	5	4
Hyperhidrosis	2	4	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

Adverse reactions in Study 2, a 1-year active-controlled (vs. interferon beta-1a, 30 mcg once weekly intramuscular injection, n=338) study including 339 patients with MS treated with Rebif were generally similar to those in Study 1, taking into account the disparity in study durations.

Anaphylaxis and other allergic reactions have been observed with the use of Rebif [see Warnings and Precautions (5.3)]. 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 three times per week doses, respectively, at one or more times during the study. 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.

The following adverse reactions have been identified during post-approval use of Rebif. 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.

Autoimmune Disorders: Drug-induced lupus erythematosus, autoimmune hepatitis

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

Skin and Subcutaneous Tissue Disorders: Erythema multiforme, Stevens-Johnson syndrome

 

 

 

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. Rebif should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In a study in pregnant cynomolgus monkeys, interferon beta was administered daily (intramuscular doses approximately 1, 2, and 7 times the maximum recommended cumulative weekly human dose, based on body surface area) either throughout the period of organogenesis or later in pregnancy (gestation day 90 to term). No adverse effects on embryofetal development were observed; however, the possibility of adverse effects cannot be ruled out because of the small number of animals tested (six per dose group at each developmental period).

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.

Safety and effectiveness in pediatric patients have not been established.

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.

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 contains approximately 2.4 million international units, 6 million international units or 12 million international units, respectively, of antiviral activity using this method.

Rebif (interferon beta-1a) is formulated as a sterile solution in a prefilled syringe or Rebif Rebidose autoinjector 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 mg or 4 mg albumin (human), 27.3 mg mannitol, 0.4 mg sodium acetate, and water for injection. Each 0.2 mL (0.2 cc) of Rebif contains 8.8 mcg of interferon beta-1a, 0.8 mg albumin (human), 10.9 mg mannitol, 0.16 mg sodium acetate, and water for injection.

 

The mechanism(s) by which Rebif (interferon beta-1a) exerts its therapeutic effects in patients with multiple sclerosis is unknown.

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.

The pharmacokinetics of Rebif (interferon beta-1a) in people with multiple sclerosis have not been evaluated. In healthy 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 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.

Carcinogenesis: Rebif has not been tested for carcinogenic potential in animals.

Mutagenesis: Interferon beta was negative in an in vitro bacterial reverse mutation (Ames) assay and an in vitro cytogenetic assay in human lymphocytes in the presence and absence of metabolic activation.

Impairment of Fertility: In studies in normally cycling female cynomolgus monkeys given daily subcutaneous injections of interferon beta 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. In male monkeys, the same doses of interferon beta had no demonstrable adverse effects on sperm count, motility, morphology, or function.

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. Patients with secondary progressive multiple sclerosis were excluded from the study. Patients received subcutaneous injections of either placebo (n = 187), Rebif 22 mcg (n = 189), or Rebif 44 mcg (n = 184) administered three times per week 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 (2.1)].

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 one 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 4 and Figure 1. Rebif at doses of 22 mcg and 44 mcg administered three times per week 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 4: Clinical and MRI Endpoints from Study 1
* Intent-to-treat analysis † Poisson regression model adjusted for center and time on study ‡ p<0.001 compared to placebo § p<0.0001 compared to placebo ¶ Logistic regression adjusted for center. Patients lost to follow-up prior to an exacerbation were excluded from this analysis. (Analysis included 185, 183, and 184 patients for three times per week placebo, 22 mcg Rebif, and 44 mcg Rebif, respectively). # p<0.05 compared to placebo Þ Cox proportional hazard model adjusted for center ß ANOVA on ranks adjusted for center. Patients with missing scans were excluded from this analysis.
	Placebo	Rebif 22 mcg	Rebif 44 mcg
	n = 187	n = 189	n = 184
Exacerbation-related
Mean number of exacerbations per patient over 2 years*,†	2.56	1.82‡	1.73§
(Percent reduction)		(29%)	(32%)
Percent (%) of patients exacerbation-free at 2 years¶	15%	25%#	32%§
Median time to first exacerbation (months)*,Þ	4.5	7.6‡	9.6§
MRI	n = 172	n = 171	n = 171
Median percent (%) change of MRI PD-T2 lesion area at 2 yearsß	11.0%	-1.2%§	-3.8%§
Median number of active lesions per patient per scan (PD/T2; 6 monthly)ß	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.

Figure 1: Proportions of Patients with Sustained Disability Progression

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. 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 three times per week subcutaneous injections of Rebif 44 mcg (n=339) or once weekly intramuscular injections of 30 mcg AVONEX (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 three times per week were more likely to remain relapse-free at 24 and 48 weeks than were patients treated with AVONEX 30 mcg once per week (Table 5). This study does not support any conclusion regarding effects on the accumulation of physical disability.

Table 5: Clinical and MRI Results from Study 2
	Rebif 44 mcg	AVONEX 30 mcg	Absolute Difference	Risk of relapse on Rebif relative to AVONEX
* Logistic regression model adjusted for treatment and center, intent to treat analysis † p <0.001 (Rebif compared to AVONEX) ‡ p = 0.009 (Rebif compared to AVONEX) § Nonparametric ANCOVA model adjusted for treatment and center, with baseline combined unique lesions as the single covariate
Relapses	N=339	N=338
Proportion of patients relapse-free at 24 weeks*	75%†	63%	12% (95% CI: 5%, 19%)	0.68 (95% CI: 0.54, 0.86)
Proportion of patients relapse-free at 48 weeks	62%‡	52%	10% (95% CI: 2%, 17%)	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 scan§ (25th, 75th percentiles)	N=325 0.17† (0.00, 0.67)	N=325 0.33 (0.00, 1.25)

Rebif is supplied as a sterile solution containing no preservative available in the following package presentations:

Prefilled Syringes:

 

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

-

Six Rebif 8.8 mcg prefilled syringes and Six Rebif 22 mcg prefilled syringes

 

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

Rebif Rebidose Autoinjectors:

 

Rebif Rebidose (interferon beta-1a) Titration Pack, NDC 44087-0188-1

-

Six Rebif Rebidose 8.8 mcg autoinjectors with lime-green injector buttons and Six Rebif Rebidose 22 mcg with yellow injector buttons.

 

Rebif Rebidose (interferon beta-1a) 22 mcg Autoinjector

-

Twelve Rebif Rebidose 22 mcg autoinjectors with yellow injector buttons, NDC 44087-3322-1

 

Rebif Rebidose (interferon beta-1a) 44 mcg Autoinjector

-

Twelve Rebif Rebidose 44 mcg autoinjectors with teal-green injector buttons, NDC 44087-3344-1

 

 

 

 

Rebif should be stored refrigerated between 36°F to 46°F (2°C to 8°C). DO NOT FREEZE. If needed, Rebif may be stored between 36°F to 77°F (2°C to 25°C) for up to 30 days and away from heat and light, but refrigeration is preferred.

Do not use beyond the expiration date printed on packages. Rebif contains no preservatives. Each prefilled syringe and Rebif Rebidose autoinjector is intended for a single dose. Unused portions should be discarded.

See FDA-approved patient labeling (Medication Guide).

Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking Rebif. Instruct patients to take Rebif only as prescribed.

Depression and Suicide

Advise patients that depression, suicidal ideation, and suicide have been reported during the use of Rebif. Inform patients of the symptoms of depression and suicidal ideation and instruct patients to immediately report any of these symptoms to their healthcare provider [see Warnings and Precautions (5.1)].

Hepatic Injury

Advise patients that severe liver injury, including hepatic failure, has been reported with the use of Rebif. Educate patients about the symptoms of hepatic injury and instruct patients to report them immediately to their healthcare provider [see Warnings and Precautions (5.2)].

Anaphylaxis and Other Allergic Reactions

Advise patients of the symptoms of allergic reactions and anaphylaxis, and instruct patients to seek immediate medical attention if these symptoms occur [see Warnings and Precautions (5.3)].

Injection Site Reactions including Necrosis

Advise patients that injection site reactions occur in most patients treated with Rebif and that injection site necrosis may occur [see Warnings and Precautions (5.4)]. Instruct patients to promptly report any break in the skin, which may be associated with blue-black discoloration, swelling, or drainage of fluid from the injection site, prior to continuing their Rebif therapy.

To minimize the likelihood of injection site reactions, inform patients of the importance of rotating injection sites with each dose and the use of aseptic injection technique [see Dosage and Administration (2.2)]. Advise patients not to re-use needles or syringes and instruct patients on safe disposal procedures. Provide appropriate instruction for self-injection of Rebif and Rebif Rebidose, including careful review of the Rebif Medication Guide.

Decreased Peripheral Blood Counts

Advise patients that they may develop a lowering of their peripheral blood counts, including their white blood counts, red blood counts, and platelets, and that their blood counts will be checked during therapy with Rebif. Inform patients that they may be more likely to get infections, anemia, or be at risk for bleeding, and that they should contact their healthcare provider if they develop symptoms of these adverse reactions [see Warnings and Precautions (5.5)].

Seizures

Instruct patients to report seizures immediately to their healthcare provider [see Warnings and Precautions (5.7)].

Flu-like Symptoms

Inform patients that flu-like symptoms are common following initiation of therapy with Rebif. Advise patients that concurrent use of analgesics and/or antipyretics may help reduce flu-like symptoms on treatment days [see Dosage and Administration (2.3)].

Risk in Pregnancy

Advise patients that Rebif should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.1)]. Therefore, inform patients that if a pregnancy is considered, or does occur, the risks and benefits of continuing Rebif should be discussed with their healthcare provider.

Manufactured by EMD Serono, Inc.Rockland,MA02370U.S.License # 1773

Marketed by:

EMD Serono, Inc.
Rockland,MA02370

Revised: 11/2015

*AVONEX is a registered trademark of Biogen

N67Z0104G

 

 

 

MEDICATION GUIDE
Rebif
interferon beta-1a
Injection for subcutaneous use

Read this Medication Guide before you start using Rebif and each time you get a refill. There may be new information. The information does not take the place of talking with your healthcare provider about your medical condition or your treatment.

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

Rebif can cause serious side effects. Tell your healthcare provider right away if you have any of the symptoms listed below while taking Rebif.

1.

Behavioral health problems including depression and suicidal thoughts. You may have mood problems including:

·   depression (feeling hopeless or feeling bad about yourself)

·   thoughts of hurting yourself or suicide

2.

Liver problems or worsening of liver problems including liver failure. Symptoms may include:

·                                 nausea ·                                 loss of appetite ·                                 tiredness ·                                 dark colored urine and pale stools	·                                 yellowing of your skin or the white part of your eye ·                                 bleeding more easily than normal ·                                 confusion ·                                 sleepiness
During your treatment with Rebif you will need to see your healthcare provider regularly and have regular blood tests to check for side effects.

3.

Serious allergic and skin reactions. Symptoms may include:

·   itching

·   swelling of your face, eyes, lips, tongue or throat

·   trouble breathing

·   anxiousness

·   feeling faint

·   skin rash, hives, sores in your mouth, or skin blisters and peels

4.

Injection site problems. Symptoms at the injection site may include:

·   redness

·   pain

·   swelling

·   color changes (blue or black)

·   drainage of fluid

What is Rebif?

Rebif is a prescription medicine used to treat adults with relapsing forms of multiple sclerosis (MS). It is a form of protein called beta interferon that is produced in the body.

Rebif 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.

The way Rebif works in MS is not known.

It is not known if Rebif is safe and effective in children.

Who should not take Rebif?

Do not take Rebif if you:

· are allergic to interferon beta, human albumin, or any of the ingredients in Rebif. See the end of this Medication Guide for a complete list of ingredients in Rebif.

What should I tell my healthcare provider before taking Rebif?

Before you take Rebif, tell your healthcare provider if have or have had any of the following conditions:

· mental illness, including depression and suicidal behavior

· liver problems

· bleeding problems or blood clots

· low blood cell counts

· seizures (epilepsy)

· thyroid problems

· drink alcohol

· you are pregnant or plan to become pregnant. (It is not known if Rebif will harm your unborn baby. Tell your healthcare provider if you become pregnant during your treatment with Rebif.)

· you are breastfeeding or plan to breastfeed. (It is not known if Rebif passes into your breast milk. You and your healthcare provider should decide if you will use Rebif or breastfeed. You should not do both.)

 

 

 

Tell your healthcare provider about all medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements.

Rebif and other medicines may affect each other causing side effects.

Ask your healthcare provider or pharmacist for a list of these medicines, if you are not sure.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

How should I use Rebif?

See the Instructions for Use at the end of this Medication Guide on how to prepare and give an injection of Rebif using a prefilled syringe. For the Rebif Rebidose autoinjector, read the Instructions for Use that comes with the Rebif Rebidose autoinjector.Your healthcare provider should show you how to prepare and measure your dose of Rebif and how to inject your Rebif before you use it for the first time.Rebif is given by injection under the skin (subcutaneous injection) on the same 3 days a week, for example, Monday, Wednesday and Friday.Your injections should be at least 48 hours apart. Take them the same time each day.Inject Rebif exactly as your healthcare provider tells you.Your healthcare provider will tell you how much Rebif to inject, and may change the dose based on how your body responds. Do not inject more than your healthcare provider tells you to.Do not change your dose unless your healthcare provider tells you to.

o    Change (rotate) your injection site you choose with each injection. This will help decrease the chance that you will have an injection site reaction.

o    Do not inject Rebif into an area of the body where the skin is irritated, reddened, bruised, infected or scarred in any way.

o    Rebif comes as a:

o        prefilled syringe (Rebif)

o        single-use prefilled autoinjector (Rebif Rebidose autoinjector)

Your healthcare provider will decide which is best for you. Always use a new, unopened, prefilled syringe of Rebif or Rebif Rebidose autoinjector for each injection. Do not reuse prefilled syringes or Rebif Rebidose autoinjectors.

What are the possible side effects of Rebif?

Rebif may cause serious side effects, including:

See "What is the most important information I should know about Rebif?"Blood problems. Rebif can affect your bone marrow and cause low red and white blood cell, and platelet counts. In some people, these blood cell counts may fall to dangerously low levels. If your blood cell counts become very low, you can get infections and problems with bleeding and bruising. Your healthcare provider may ask you to have regular blood tests to check for blood problems.Seizures. Some people have had seizures while taking Rebif.

The most common side effects of Rebif include:

flu-like symptoms. You may have flu-like symptoms when you first start taking Rebif. You may be able to manage these flu-like symptoms by taking over-the-counter pain and fever reducers. For many people, these symptoms lessen or go away over time. Symptoms may include:

o    muscle aches

o    fever

o    tiredness

o    chills

stomach painchange in liver blood tests

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

These are not all the possible side effects of Rebif. For more information, ask your healthcare provider or pharmacist.

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

How should I store Rebif?

Store Rebif in the refrigerator between 36°F to 46°F (2°C to 8°C).Do not freeze Rebif.If you cannot refrigerate your Rebif, you can store your Rebif at temperatures above 36°F and below 77°˚F (2°C to 25°C) for up to 30 days.Keep Rebif away from heat and light.

 

 

 

 

Keep Rebif and all medicines out of the reach of children.

General information about the safe and effective use of Rebif

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Rebif for a condition for which it was not prescribed. Do not give Rebif to other people, even if they have they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about Rebif. If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about Rebif that is written for healthcare professionals.

For more information, go to www.Rebif.com or call toll-free 1-877-447-3243.

What are the ingredients in Rebif?

Active ingredient: interferon beta-1a

Inactive ingredients: albumin (human), mannitol, sodium acetate, water for injection

Instructions for Use
Rebif (Re-bif)
interferon beta-1a
(in-ter-feer-on beta-one-â)
Injection for subcutaneous use
Prefilled Syringe

Read and follow the Instructions for Use that come with your Rebif prefilled syringe before you start using it and each time you get a refill. Before you use a Rebif prefilled syringe for the first time, make sure your healthcare provider shows you the right way to use it.

Important: For the Rebif Rebidose autoinjector, read the Instructions for Use that come with the Rebif Rebidose autoinjector.

Parts of your Rebif Prefilled Syringe (See Figure A).

Figure A

Supplies needed for a Rebif Injection (See Figure B):

Rebif prefilled syringealcohol pad or cotton balls and rubbing alcoholsmall adhesive bandage strip if desiredpuncture resistant safety container for disposal of used syringes. See "Disposing of your Needles and Syringes Section" in Step 4 of the IFU.antibacterial soapan over-the-counter pain or fever reducing medicine, if your healthcare provider has recommended that you take this before, at the same time, or after you give yourself Rebif to help decrease the fever, chills, sweating and muscle aches (flu-like symptoms) that may happen.

Figure B

Titration (Dosing) Schedule

When first starting treatment with Rebif, your healthcare provider 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 healthcare provider.

If your prescribed dose is 22 mcg of Rebif, a Rebif Titration Pack containing 6 prefilled syringes with 8.8 mcg and 6 prefilled syringes with 22 mcg should be prescribed to you for use during the 4-week starting period. Table 1 explains the amount to inject using the Rebif Titration Pack syringes to gradually increase to 22 mcg.

Table 1: Titration Schedule for a 22 mcg Prescribed Dose*
Week of Use	Syringe to Use	Amount of syringe
* Only prefilled syringes can be used to titrate to the 22 mcg Prescribed Dose
Week 1 Titration	8.8 mcg syringe	Use half of syringe
Week 2 Titration	8.8 mcg syringe	Use half of syringe
Week 3 Titration	22 mcg syringe	Use half of syringe
Week 4 Titration	22 mcg syringe	Use half of syringe
Week 5 and on	22 mcg syringe or autoinjector	Use full syringe or autoinjector

If your prescribed dose is 44 mcg, you may be prescribed either a Rebif Titration Pack (described above) or Rebif Rebidose Titration Pack containing 6 autoinjectors with 8.8 mcg and 6 autoinjectors with 22 mcg for use during the 4 week titration period. Table 2 explains the amount to inject using the Rebif Titration Pack or Rebif Rebidose Titration Pack to gradually increase to 44 mcg.

 

 

Table 2: Titration Schedule for a 44 mcg Prescribed Dose*
Week of Use	Syringe or Autoinjector to Use	Amount of syringe or autoinjector
* Prefilled syringes or autoinjectors can be used to titrate to 44 mcg Prescribed Dose
Week 1 Titration	8.8 mcg syringe or autoinjector	Use full syringe or autoinjector
Week 2 Titration	8.8 mcg syringe or autoinjector	Use full syringe or autoinjector
Week 3 Titration	22 mcg syringe or autoinjector	Use full syringe or autoinjector
Week 4 Titration	22 mcg syringe or autoinjector	Use full syringe or autoinjector
Week 5 and on	44 mcg syringe or autoinjector	Use full syringe or autoinjector

Step 1. Preparing for your Rebif Injection

Check the expiration date. Do not use if the medication is expired. The expiration date is printed on the syringe, plastic syringe packaging and carton.Remove your Rebif syringe from the refrigerator at least 30 minutes before you plan to use it so it can warm to room temperature. Do not heat or microwave the medication.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 healthcare provider.Remove the Rebif syringe from the plastic packaging. Keep the needle capped.Look at 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. Use a different syringe.

Step 2. Choose and Prepare your 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 waistline or within 2 inches of your navel. 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 such as the thigh, hip, stomach or upper arm (See Figure C).

Figure C

Do not inject Rebif into an area of your body where the skin is irritated, reddened, bruised, infected or abnormal in any way.Wash your hands thoroughly with antibacterial soap before preparing to inject the medicine.Clean the injection site with an alcohol pad or cotton ball with rubbing alcohol using a circular motion. To avoid stinging, you should let your skin dry before you inject Rebif.

Step 3. Inject your Rebif

Remove the needle cap from the syringe needle.If your healthcare provider has told you to use less than the full 0.5 mL dose, slowly push the plunger in until the amount of medicine left in the syringe is the amount healthcare provider told you to use.Use your thumb and forefinger to pinch a pad of skin surrounding the cleaned injection site (See Figure D). Hold the syringe like a pencil with your other hand.

Figure D

While still pinching the skin, quickly insert the needle like a dart at about a 90 degree angle (just under the skin) into the pad of tissue as shown (See Figure E).

Figure E

After the needle is in, remove the hand that you used to pinch your skin and inject the medicine using a slow, steady push on the plunger until all the medicine is injected and the syringe is empty (See Figure F).

Figure F

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.Keep a record of the date and location of each injection.After 2 hours, check the injection site for redness, swelling, or tenderness. If you have a skin reaction and it does not clear up in a few days, call your healthcare provider.

 

 

 

 

Step 4. Disposing of your Needles and Syringes

Put your used needles, syringes, and autoinjectors, including Rebif, in an FDA-cleared sharps container right away after use. Do not throw away (dispose of) any syringes or autoinjectors in your household trash.
If you do not have an FDA-cleared sharps disposal container, you may use a household container that is:

o    made of a heavy-duty plastic,

o    closed with a tight-fitting, puncture-resistant lid,

o    upright and stable during use,

o    leak-resistant, and

o    properly labeled to warn of hazardous waste inside the container.

When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used autoinjectors and syringe needles. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal.Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.

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

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

Marketed by:
EMD Serono, Inc.
Rockland, MA 02370

Revised November 2015

Rebif® Titration Pack
(interferon beta-1a)

NDC 44087-8822-1

8.8 mcg/0.2 mL
22 mcg/0.5 mL

For subcutaneous injection
Rx Only
Medication Guide for patients enclosed

6 Single-use 8.8 mcg/0.2 mL prefilled syringes
6 Single-use 22 mcg/0.5 mL prefilled syringes

EMD Serono

Rebif® Rebidose® 
(interferon beta-1a)
Injection

NDC 44087-0188-1

6 single-use 8.8 mcg / 0.2 mL autoinjectors
6 single-use 22 mcg / 0.5 mL autoinjectors

8.8 mcg / 0.2 mL

Rx only

22 mcg / 0.5 mL

Titration Pack
For subcutaneous injection

Attention pharmacist:
Each patient is required to receive
the enclosed Medication Guide

EMD Serono

Rebif® 22 mcg/0.5 mL
(interferon beta-1a)

NDC 44087-0022-3

For subcutaneous injection
Rx only
Medication Guide for patients enclosed

12 Single-use prefilled syringes

EMD Serono

Rebif® 44 mcg/0.5 mL
(interferon beta-1a)

NDC 44087-0044-3

For subcutaneous injection
Rx only
Medication Guide for patients enclosed

12 Single-use prefilled syringes

EMD Serono

NDC 44087-3322-1

Rebif® Rebidose®
(interferon beta-1a)
Injection

12 single-use autoinjectors

22 mcg / 0.5 mL
For subcutaneous injection

Rx only

Attention pharmacist: Each patient is required
to receive the enclosed Medication Guide

EMD Serono

NDC 44087-3344-1

Rebif® Rebidose®
(interferon beta-1a)
Injection

12 single-use autoinjectors

44 mcg / 0.5 mL
For subcutaneous injection

Rx only

Attention pharmacist: Each patient is required
to receive the enclosed Medication Guide

EMD Serono

Rebif interferon beta-1a kit

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:44087-8822

Packaging # Item Code Package Description   1 NDC:44087-8822-1 1 KIT in 1 CARTON

Quantity of Parts Part # Package Quantity Total Product Quantity     Part 1 6 SYRINGE, GLASS 1.2 mL     Part 2 6 SYRINGE, GLASS 3 mL

Part 1 of 2 Rebif interferon beta-1a injection, solution

Product Information         Route of Administration SUBCUTANEOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength INTERFERON BETA-1A (INTERFERON BETA-1A) INTERFERON BETA-1A 8.8 ug  in 0.2 mL

Inactive Ingredients Ingredient Name Strength MANNITOL 10.9 mg  in 0.2 mL ALBUMIN HUMAN 0.8 mg  in 0.2 mL SODIUM ACETATE 0.16 mg  in 0.2 mL WATER

Packaging # Item Code Package Description   1   0.2 mL in 1 SYRINGE, GLASS

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA103780 12/17/2004

Part 2 of 2 Rebif interferon beta-1a injection, solution

Product Information         Route of Administration SUBCUTANEOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength INTERFERON BETA-1A (INTERFERON BETA-1A) INTERFERON BETA-1A 22 ug  in 0.5 mL

Inactive Ingredients Ingredient Name Strength MANNITOL 27.3 mg  in 0.5 mL ALBUMIN HUMAN 2 mg  in 0.5 mL SODIUM ACETATE 0.4 mg  in 0.5 mL WATER

Packaging # Item Code Package Description   1   0.5 mL in 1 SYRINGE, GLASS

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA103780 12/17/2004

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA103780 12/17/2004

Rebif REBIDOSE interferon beta-1a kit

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:44087-0188

Packaging # Item Code Package Description   1 NDC:44087-0188-1 1 KIT in 1 CARTON

Quantity of Parts Part # Package Quantity Total Product Quantity     Part 1 6 PACKAGE 1.2 mL     Part 2 6 PACKAGE 3 mL

Part 1 of 2 Rebif REBIDOSE interferon beta-1a injection, solution

Product Information         Route of Administration SUBCUTANEOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength INTERFERON BETA-1A (INTERFERON BETA-1A) INTERFERON BETA-1A 8.8 ug  in 0.2 mL

Inactive Ingredients Ingredient Name Strength MANNITOL 10.9 mg  in 0.2 mL ALBUMIN HUMAN 0.8 mg  in 0.2 mL SODIUM ACETATE 0.16 mg  in 0.2 mL WATER

Packaging # Item Code Package Description   1   0.2 mL in 1 PACKAGE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA103780 12/21/2012

Part 2 of 2 Rebif REBIDOSE interferon beta-1a injection, solution

Product Information         Route of Administration SUBCUTANEOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength INTERFERON BETA-1A (INTERFERON BETA-1A) INTERFERON BETA-1A 22 ug  in 0.5 mL

Inactive Ingredients Ingredient Name Strength MANNITOL 27.3 mg  in 0.5 mL ALBUMIN HUMAN 2 mg  in 0.5 mL SODIUM ACETATE 0.4 mg  in 0.5 mL WATER

Packaging # Item Code Package Description   1   0.5 mL in 1 PACKAGE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA103780 12/21/2012

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA103780 12/21/2012

Rebif interferon beta-1a injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:44087-0022 Route of Administration SUBCUTANEOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength INTERFERON BETA-1A (INTERFERON BETA-1A) INTERFERON BETA-1A 22 ug  in 0.5 mL

Inactive Ingredients Ingredient Name Strength ALBUMIN HUMAN 2 mg  in 0.5 mL MANNITOL 27.3 mg  in 0.5 mL SODIUM ACETATE 0.4 mg  in 0.5 mL WATER

Packaging # Item Code Package Description   1 NDC:44087-0022-3 12 SYRINGE, GLASS in 1 CARTON   1 NDC:44087-0022-9 0.5 mL in 1 SYRINGE, GLASS

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA103780 03/07/2002

Rebif interferon beta-1a injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:44087-0044 Route of Administration SUBCUTANEOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength INTERFERON BETA-1A (INTERFERON BETA-1A) INTERFERON BETA-1A 44 ug  in 0.5 mL

Inactive Ingredients Ingredient Name Strength ALBUMIN HUMAN 4 mg  in 0.5 mL MANNITOL 27.3 mg  in 0.5 mL SODIUM ACETATE 0.4 mg  in 0.5 mL WATER

Packaging # Item Code Package Description   1 NDC:44087-0044-3 12 SYRINGE, GLASS in 1 CARTON   1 NDC:44087-0044-9 0.5 mL in 1 SYRINGE, GLASS

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA103780 03/07/2002

Rebif REBIDOSE interferon beta-1a injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:44087-3322 Route of Administration SUBCUTANEOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength INTERFERON BETA-1A (INTERFERON BETA-1A) INTERFERON BETA-1A 22 ug  in 0.5 mL

Inactive Ingredients Ingredient Name Strength ALBUMIN HUMAN 2 mg  in 0.5 mL MANNITOL 27.3 mg  in 0.5 mL SODIUM ACETATE 0.4 mg  in 0.5 mL WATER

Packaging # Item Code Package Description   1 NDC:44087-3322-1 12 PACKAGE in 1 CARTON   1 NDC:44087-3322-9 0.5 mL in 1 PACKAGE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA103780 12/21/2012

Rebif REBIDOSE interferon beta-1a injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:44087-3344 Route of Administration SUBCUTANEOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength INTERFERON BETA-1A (INTERFERON BETA-1A) INTERFERON BETA-1A 44 ug  in 0.5 mL

Inactive Ingredients Ingredient Name Strength ALBUMIN HUMAN 4 mg  in 0.5 mL MANNITOL 27.3 mg  in 0.5 mL SODIUM ACETATE 0.4 mg  in 0.5 mL WATER

Packaging # Item Code Package Description   1 NDC:44087-3344-1 12 PACKAGE in 1 CARTON   1 NDC:44087-3344-9 0.5 mL in 1 PACKAGE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA103780 12/21/2012

Labeler - EMD Serono, Inc. (088514898)

Revised: 01/2016

 

EMD Serono, Inc.