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BENLYSTA(belimumab)for injection

2014-05-03 19:09:01 来源: 作者: 【大中小】浏览:1905次评论:0条

Human Genome Sciences, Inc.
BENLYSTA- belimumab injection, powder, lyophilized, for solution
Human Genome Sciences, Inc.
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use BENLYSTA safely and effectively. See full prescribing information for BENLYSTA.
BENLYSTA® (belimumab)
for injection, for intravenous use only
Initial U.S. Approval: 2011
RECENT MAJOR CHANGES
Warning and Precautions ( 5.4) 03/2012
INDICATIONS AND USAGE
BENLYSTA is a B-lymphocyte stimulator (BLyS)-specific inhibitor indicated for the treatment of adult patients with active, autoantibody-positive, systemic lupus erythematosus who are receiving standard therapy. ( 1, 14)
Limitations of Use: The efficacy of BENLYSTA has not been eva luated in patients with severe active lupus nephritis or severe active central nervous system lupus ( 1). BENLYSTA has not been studied in combination with other biologics or intravenous cyclophosphamide (1). Use of BENLYSTA is not recommended in these situations.
DOSAGE AND ADMINISTRATION
■Recommended dosage regimen is 10 mg/kg at 2-week intervals for the first 3 doses and at 4-week intervals thereafter. Reconstitute, dilute and administer as an intravenous infusion only, over a period of 1 hour. (2.1)
■Consider administering premedication for prophylaxis against infusion reactions and hypersensitivity reactions (2.2)
DOSAGE FORMS AND STRENGTHS
Single-use vials of belimumab lyophilized powder:
■120 mg per vial (3)
■400 mg per vial (3)
CONTRAINDICATIONS
Previous anaphylaxis to belimumab. ( 4)
WARNINGS AND PRECAUTIONS
■Mortality: There were more deaths reported with BENLYSTA than with placebo during the controlled period of clinical trials. (5.1)
■Serious Infections: Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents, including BENLYSTA. Use with caution in patients with chronic infections. Consider interrupting BENLYSTA therapy if patients develop a new infection during BENLYSTA treatment. (5.2)
■Hypersensitivity Reactions, Including Anaphylaxis: Serious and fatal reactions have been reported. BENLYSTA should be administered by healthcare providers prepared to manage anaphylaxis. Monitor patients during and for an appropriate period of time after administration of BENLYSTA. (2.2, 5.4)
■Depression: Depression and suicidality have been reported in BENLYSTA studies. Patients should be instructed to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts or other mood changes. (5.6)
■Immunization: Live vaccines should not be given concurrently with BENLYSTA. (5.7)
ADVERSE REACTIONS
Common adverse reactions (≥5%) in clinical trials were: nausea, diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, pain in extremity, depression, migraine, and pharyngitis. ( 6.1)
To report SUSPECTED ADVERSE REACTIONS, contactHuman Genome Sciences, Inc. at 1-877-423-6597or FDA at 1-800-FDA-1088 orwww.fda.gov/medwatch.
USE IN SPECIFIC POPULATIONS
■Pregnancy: Registry available. (8.1)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 03/2012
完整处方资料
1 适应证和用途
BENLYSTA® (belimumab)适用于治疗活动性，自身抗体-阳性，全身性红斑狼疮(SLE)正在接受标准治疗的成年患者。
使用限制
未曾在有严重活动性狼疮肾炎或严重活动性中枢神经系统狼疮患者中评价BENLYSTA的疗效。未曾研究BENLYSTA与其它生物制品s或静脉环磷酰胺的联用。不建议在这些情况中使用BENLYSTA。
2 剂量和给药方法
2.1 用药方案
BENLYSTA是只为静脉输注和给药前必须配制和稀释[见剂量和给药方法2.3)]，不要静脉推注或丸注给药。.
推荐给药方案是头3剂每间隔2-周10 mg/kg而其后间隔4-周。配制，稀释和只作为在1小时期间静脉输注给药。如患者发生输注反应输注速率可减慢或中断。如患者经受严重超敏反应，必须立即终止输注[见禁忌证(4)，警告和注意事项(5.4)]。
2.2 建议预先给药
Prior to dosing 用BENLYSTA给药前，为预防输注反应和超敏性反应考虑预防给药。[见警告和注意事项(5.4,5.5)和不良反应(6.1)]。
2.3 溶液的配制
BENLYSTA为冻干粉在只为静脉输注单次使用小瓶内供应并应由医疗保健人员用无菌术配制和稀释如下：
配制指导
1. 从冰箱取出BENLYSTA和允许放置10至15分钟使小瓶达到室温。
2. 用注射用无菌水，USP，配制BENLYSTA粉如下。配制好溶液含浓度80 mg/mL belimumab。
（1）配制120 mg小瓶用1.5 mL注射用无菌水，USP。
（2）配制400 mg小瓶用4.8 mL注射用无菌水，USP。
3. 为缩少起泡，无菌水流直接注向小泡侧壁。轻轻旋转小瓶60秒。配制期间允许小瓶放在室温，每隔5分钟轻轻旋转小瓶60秒直至粉溶解。不要振荡。典型地是在无菌水加入后10至15分钟完成，但可能需要30分钟。保护配制溶液免受阳光。
4. 如果使用机械配制设备(旋流器)配制BENLYSTA，其转速不应超过500 rpm和小瓶旋转时间不长于30分钟。
5. 一旦配制完成，溶液应是发乳白色光和无色至浅黄色，和无颗粒。小空气泡，然而，是预期和可接受的。
稀释指导
6. 静脉葡萄糖溶液与BENLYSTA不兼容。BENLYSTA只应被稀释在0.9%氯化钠注射液，USP。为静脉输注稀释配制好产品至250 mL在0.9%氯化钠注射液，USP(生理盐水)。从一个250-mL输注袋或瓶生理盐水，抽吸和遗弃与患者需要剂量的配制好BENLYSTA溶液等同体积。然后加入需要体积的配制好BENLYSTA溶液至输注袋或瓶。轻轻倒置袋或瓶混匀溶液。必须遗弃小瓶内任何未使用溶液。
7. 非肠道给药产品在给药前无论何时只要容器和溶液允许，应肉眼观测颗粒物质和变色。如观察到任何颗粒物质或变色丢弃溶液。
8. BENLYSTA的配制溶液，如不是立即使用保护避免直接阳光贮存和冰箱在2°至8°C(36°至46°F)。生理盐水稀释好的BENLYSTA溶液可贮存在2°至8°C(36°至46°F)或室温。从配制BENLYSTA至完成输注的总时间不应超过8个小时。
9.曾观察到BENLYSTA和聚氯乙烯或聚烯烃输液袋间无不兼容性。
2.4 给药指导
1. 稀释好的BENLYSTA溶液只应在1小时期间经静脉输注给药。
2. 应由医疗保健人员BENLYSTA给药和准备处理过敏反应。[见警告和注意事项(5.4)]
3. 其它药物不应与BENLYSTA同时在相同静脉线输注。未曾进行物理或生化兼容性研究评价BENLYSTA与其它药物的的共同给药。
3 剂型和规格
注射用belimumab冻干粉单次使用小瓶：
（1）120 mg每小瓶
（2）400 mg每小瓶
4 禁忌证
曾有与belimumab过敏反应患者禁忌BENLYSTA。
5 警告和注意事项
5.1 死亡率
临床试验的对照阶段期间用BENLYSTA比用安慰剂有更多死亡报道。在3项临床试验2133例患者中，在安慰剂-对照，双盲治疗阶段总共发生14例死亡：安慰剂，BENLYSTA 1 mg/kg，BENLYSTA 4 mg/kg，和BENLYSTA 10 mg/kg组死亡分别为3/675(0.4%)，5/673(0.7%)，0/111(0%)，和6/674 (0.9%)。没有单一为主的死亡原因。病因包括感染，心血管病和自杀。
5.2 严重感染
在接受免疫抑制剂患者中，包括BENLYSTA曾报道严重和有时致命性感染。有慢性感染患者中当考虑使用BENLYSTA时医生应谨慎。对接受任何治疗的慢性感染患者不应开始用BENLYSTA治疗。当正在用BENLYSTA进行治疗患者发生某种新感染考虑中断BENLYSTA治疗并且严密监视这些患者。
在对照临床试验中，在用BENLYSTA治疗患者中感染的总发生率为71%相比较在接受安慰剂患者中67%。最频的感染(接受BENLYSTA患者>5%)是上呼吸道感染，泌尿道感染，鼻咽炎，窦炎，支气管炎，和流感。用BENLYSTA治疗患者发生严重感染6.0%和接受安慰剂患者为5.2%。最频严重感染包括肺炎，泌尿道感染，蜂窝组织炎，和支气管炎。接受BENLYSTA患者0.7%的感染导致发生终止治疗和接受安慰剂患者为1.0%。用BENLYSTA治疗0.3%(4/1458)患者因感染导致发生死亡而接受安慰剂患者为0.1%(1/675)。
5.3 恶性病
用BENLYSTA治疗对恶性病发生的影响不知道。在对照临床试验中，接受BENLYSTA患者报道恶性病(包括非黑色素瘤皮肤癌)0.4%和接受安慰剂患者0.4%。在对照临床试验中，接受BENLYSTA患者和安慰剂, 分别观察到0.2%(3/1458)和0.3% (2/675)恶性病，除外非黑色素瘤皮肤癌。如同其它免疫调节药物，BENLYSTA的作用机制可能增加发生恶性病的风险。
5.4 超敏性反应，包括过敏反应
在对照临床试验中，接受BENLYSTA患者报道13%(191/1458)超敏性反应(发生在输注相同天)而接受安慰剂患者报道11%(76/675)。接受BENLYSTA患者观察到0.6%(9/1458)过敏反应和接受安慰剂患者为0.4%(3/675)。表现包括低血压，血管水肿，荨麻疹或其它皮疹，瘙痒，和呼吸困难。由于征象和症状中重叠，不可能在所有病例中区别超敏性反应和输注反应[见警告和注意事项(5.5)]。有些患者(13%)接受预先给药，可能减轻或掩盖超敏性反应；然而，存在证据不够充分确定预先给药是否减弱超敏性反应的频数和严重性。
应由BENLYSTA保健提供者给药准备处理过敏反应。在严重反应事件中，必须立即终止BENLYSTA和适当医疗给药。给予BENLYSTA期间和后适当时间应监视患者。应告知患者超敏性反应征象和症状和教导发生反应时立即求医。
5.5 输注反应
在对照临床试验中，接受BENLYSTA患者报道伴随输注(发生在输注相同天)不良事件17%(251/1458)而接受安慰剂患者15%(99/675)。接受BENLYSTA患者报道严重输注反应(除外超敏性反应)0.5%和接受安慰剂患者为0.4%和包括心动过缓，肌肉痛，头痛，皮疹，荨麻疹，和低血压。最常见输注反应(接受BENLYSTA患者≥ 3%)是头痛，恶心，和皮肤反应。由于征象和症状中重叠，不可能在所有病例中区别超敏性反应和输注反应[见警告和注意事项(5.4)]. 。有些患者(13%)接受预先给药，可能减轻或掩盖输注反应；然而存在证据不够充分确定预先给药是否减弱输注反应的频数和严重性[见不良反应(6.1)]。
应由BENLYSTA保健提供者给药准备处理输注反应。如患者发生输注反应输注速率可能减慢或中断。保健提供者应认识超敏性反应的风险，可能以输注反应存在，和严密监视患者。
5.6 抑郁
在对照临床试验中，用BENLYSTA(16%)比用安慰剂(12%)报道更频精神科事件，频繁相关于抑郁-相关事件(BENLYSTA6.3%和安慰剂4.7%)，失眠(BENLYSTA6.0%和安慰剂5.3%)，和焦虑(BENLYSTA3.9%和安慰剂2.8%)。接受BENLYSTA患者报道严重精神科事件0.8%(用1和10 mg/kg分别为0.6%和1.2%)和接受安慰剂患者为0.4%。接受BENLYSTA患者报道严重抑郁0.4%(6/1458)和接受安慰剂患者为0.1%(1/675)。接受BENLYSTA患者报道两例自杀(0.1%)。报道严重抑郁或自杀行为患者的大多数有抑郁史或其它严重精神疾患和大多数接受精神病药物。不知道BENLYSTA治疗是否伴这些事件风险增加。
教导接受BENLYSTA患者如经受新或恶化的抑郁，自杀想法，或其它情绪变化应立即联系医疗保健人员。
5.7 免疫接种
用BENLYSTA当时或前30天不应给予活疫苗因尚未确定其临床安全性。没有关于接受BENLYSTA患者来自接受活疫苗人们二次传播感染或BENLYSTA对新免疫接种的影响的资料。因为其作用机制，BENLYSTA可能干预免疫接种的反应。
5.8 同时使用其它生物制品或静脉环磷酰胺治疗
尚未研究BENLYSTA与其它生物制品治疗联用，包括靶向B-细胞治疗，或静脉环磷酰胺。所以，建议BENLSTA不要与其它生物制品或静脉环磷酰胺联用。
6 不良反应
因为临床试验是在广泛不同条件下进行，某药临床试验观察到的不良反应率不能与另一药物临床试验中的发生率直接比较而且可能不反映实践中观察到的发生率。
用BENLYSTA曾观察到以下并在警告和注意事项节内详细讨论:
（1）死亡率[见警告和注意事项(5.1)]
（2）严重感染[见警告和注意事项(5.2)]
（3）恶性病[见警告和注意事项(5.3)]
（4）超敏性反应，包括过敏反应[见警告和注意事项(5.4)]
（5）输注反应 [见警告和注意事项(5.5)]
（6）抑郁[见警告和注意事项(5.6)]
6.1 临床试验经验
下面描述资料反映在3项对照研究2133例患者中暴露于BENLYSTA加医护标准与安慰剂加医护标准的比较。患者接受BENLYSTA剂量1 mg/kg(N=673)，4 mg/kg(N=111；仅试验1)，或10 mg/kg(N=674)或安慰剂 (N=675)在1小时期间静脉输注，在第0，14，28，然后每28天。在两项研究中(试验1和试验3)，治疗被给予共48周，而其它研究(试验2)治疗被给予共72周[见临床研究(14)]。因为观察到不良事件的大多数没有明显与BENLYSTA剂量相关增加，下面展示安全性资料的总结是3个剂量的合并，除非另外注明；不良反应表显示推荐剂量10 mg/kg比用安慰剂的结果。
人群平均年龄39岁(范围18-75)，94%是女性，和52%是高加索人。在这些试验中，用BENLYSTA治疗患者93%报道一种不良反应与之比较用安慰剂治疗为2% 。
最常见严重不良反应是严重感染(接受BENLYSTA和安慰剂组分别为6.0%和5.2%)[见警告和注意事项(5.2)]。
在临床试验中最常见被报道不良反应，发生≥5%患者是恶心，腹泻，发热，鼻咽炎，支气管炎，失眠，肢体疼痛，抑郁，偏头痛，和咽炎。
对照临床试验期间由于任何不良反应终止治疗的患者比例对接受BENLYSTA患者是6.2%和对接受安慰剂患者是7.1%。最常见不良反应导致终止治疗(接受BENLYSTA患者或安慰剂≥1%)为输注反应(BENLYSTA是1.6%和安慰剂0.9%)，狼疮肾炎(BENLYSTA为0.7%和安慰剂1.2%)，和感染(BENLYSTA为0.7%和安慰剂1.0%)。
表1列举在3项对照研究中，接受BENLYSTA 10 mg/kgSLE患者的至少发生3%和发生率至少比用安慰剂观察到较大1%不良反应，不管其原因。
6.2 免疫原性
在试验2和3中，接受BENLYSTA 10 mg/kg患者4/563例(0.7%)被检出抗-belimumab抗体而接受BENLYSTA 1 mg/kg患者检出27/559例(4.8%)。接受10 mg/kg组报道的频数可能比真实频数低估，由于存在高药物浓度，分析灵敏度较低。在3例接受BENLYSTA 1 mg/kg患者中被检出中和抗体。3例有抗-belimumab抗体患者经受轻度输注反应恶心，红斑皮疹，瘙痒，眼睑水肿，头痛，和呼吸困难；这些反映没有一种危及生命。不知道存在抗-belimumab抗体的临床意义。
资料反映在对belimumab抗体特异性分析中测试结果阳性患者的百分率。在某种分析中观察到抗体阳性的发生率是高度依赖于几种因素，包括分析灵敏度和特异性，分析的方法学，样品处理，采样时间，同时用药，和所患疾病。由于这些原因，比较对belimumab抗体的发生率与其它产品抗体的发生率可能是误导。
7 药物相互作用
未曾用BENLYSTA进行正式药物相互作用研究。在有SLE患者的临床试验中, BENLYSTA与其它药物同时给药，包括皮质激素，抗疟药，免疫调节和免抑制药物(包括硫唑嘌呤[azathioprine]，甲氨蝶呤[methotrexate]，和麦考酚酯[mycophenolate])，血管紧张素通路抗高血压药，HMG-CoA还原酶抑制剂(他汀类)，和NSAIDs无这些合并用药对belimumab药代动力学有临床意义的影响的证据。尚未评价belimumab对其它药物药代动力学的影响[见药代动力学 12.3]。
8 在特殊人群中使用
8.1 妊娠
妊娠类别C。没有在妊娠妇女中用BENLYSTA适当和对照良好的临床研究。免疫球蛋白G(IgG)抗体，包括BENLYSTA可跨越胎盘。因为动物生殖研究并非总能预测人类反应，在妊娠期间只有对母亲的潜在效益合理地胜过对胎儿的潜在风险才应使用BENLYSTA。有生育力妇女在用BENLYSTA治疗时和最后治疗后四个月期间应使用适当避孕。
非临床生殖研究曾进行in怀孕食蟹猴接受belimumab在剂量每2周静脉输注0，5和150 mg/kg(高剂量接近期望最大人暴露9倍)从怀孕20天至150天。Belimumab显示跨越胎盘。在试验条件下Belimumab不伴有直接或间接致畸胎性。在0，5和150 mg/kg组分别观察到怀孕雌猴的胎猴14%，24%和15%死亡。发生婴猴死亡率分别为0%，8%和5%。不知道胎猴和新生婴猴死亡的原因。不知道这些发现对人类的关联。其它治疗相关发现是限于母猴和婴猴期望的B细胞的可逆减少和在婴猴中IgM可逆减低。停止belimumab处理成年猴中产后约1年和婴猴3个月龄B-细胞数恢复。在子宫内暴露于belimumab婴猴中IgM水平于6个月龄时恢复。
妊娠注册：为监视暴露于BENLYSTA怀孕妇女的母-胎儿结局，已建立妊娠注册。医疗保健专业人员被鼓励注册患者而鼓励妊娠妇女本身通过电话1-877-681-6296注册。
8.3 哺乳母亲
不知道BENLYSTA是否被排泄至人乳汁或摄入后被全身吸收。然而，belimumab被排泄至食蟹猴乳汁。因为母体抗体被排泄至人乳房乳汁，应做出决策是否终止母乳喂养或终止药物，考虑到母乳喂养对婴儿和药物对母亲的重要性。
8.4 儿童使用
未曾确定BENLYSTA在儿童中安全性和有效性。
8.5 老年人使用
BENLYSTA的临床研究未包括足够数量年龄65或以上的受试者以确定他们是否与较年轻受试者不同。在年老患者中慎用。
8.6 种族
在试验2和试验3中，在BENLYSTA组中黑人受试者对主要终点的缓解率相对于在安慰剂组中黑人受试者较低[见临床研究(14)]。在黑人/非洲美国人患者中慎用。
10 药物过量
用BENLYSTA的药物过量无临床经验。曾通过静脉输注两次剂量达20 mg/kg至人与1，4，或10 mg/kg剂量比较未增加不良反应的发生率或严重性。
BENLYSTA
FULL PRESCRIBING INFORMATION: CONTENTS *
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Dosage Schedule
2.2 Premedication Recommendations
2.3 Preparation of Solutions
2.4 Administration Instructions
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Mortality
5.2 Serious Infections
5.3 Malignancy
5.4 Hypersensitivity Reactions, Including Anaphylaxis
5.5 Infusion Reactions
5.6 Depression
5.7 Immunization
5.8 Concomitant Use with Other Biologic Therapies or Intravenous Cyclophosphamide
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Immunogenicity
6.3 Postmarketing Experience
7 DRUG INTERACTIONS
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Race
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Advice for the Patient
PACKAGE LABEL PRINCIPLE DISPLAY PANEL
*
Sections or subsections omitted from the full prescribing information are not listed.
FULL PRESCRIBING INFORMATION

11 INDICATIONS AND USAGE

BENLYSTA ® (belimumab) is indicated for the treatment of adult patients with active, autoantibody-positive, systemic lupus erythematosus (SLE) who are receiving standard therapy.

Limitations of Use

The efficacy of BENLYSTA has not been eva luated in patients with severe active lupus nephritis or severe active central nervous system lupus. BENLYSTA has not been studied in combination with other biologics or intravenous cyclophosphamide. Use of BENLYSTA is not recommended in these situations.

22 DOSAGE AND ADMINISTRATION

2.12.1 Dosage Schedule

BENLYSTA is for intravenous infusion only and must be reconstituted and diluted prior to administration [see Dosage and Administration (2.3)]. Do not administer as an intravenous push or bolus.

The recommended dosage regimen is 10 mg/kg at 2-week intervals for the first 3 doses and at 4-week intervals thereafter. Reconstitute, dilute and administer as an intravenous infusion only, over a period of 1 hour. The infusion rate may be slowed or interrupted if the patient develops an infusion reaction. The infusion must be discontinued immediately if the patient experiences a serious hypersensitivity reaction [seeContraindications (4), Warnings and Precautions (5.4)].

2.22.2 Premedication Recommendations

Prior to dosing with BENLYSTA, consider administering premedication for prophylaxis against infusion reactions and hypersensitivity reactions. [seeWarnings and Precautions (5.4, 5.5 ) and Adverse Reactions (6.1)].

2.32.3 Preparation of Solutions

BENLYSTA is provided as a lyophilized powder in a single-use vial for intravenous infusion only and should be reconstituted and diluted by a healthcare professional using aseptic technique as follows:

Reconstitution Instructions

Remove BENLYSTA from the refrigerator and allow to stand 10 to 15 minutes for the vial to reach room temperature.
Reconstitute the BENLYSTA powder with Sterile Water for Injection, USP, as follows. The reconstituted solution will contain a concentration of 80 mg/mL belimumab.
- Reconstitute the 120 mg vial with 1.5 mL Sterile Water for Injection, USP.
- Reconstitute the 400 mg vial with 4.8 mL Sterile Water for Injection, USP.
The stream of sterile water should be directed toward the side of the vial to minimize foaming. Gently swirl the vial for 60 seconds. Allow the vial to sit at room temperature during reconstitution, gently swirling the vial for 60 seconds every 5 minutes until the powder is dissolved. Do not shake. Reconstitution is typically complete within 10 to 15 minutes after the sterile water has been added, but it may take up to 30 minutes. Protect the reconstituted solution from sunlight.
If a mechanical reconstitution device (swirler) is used to reconstitute BENLYSTA, it should not exceed 500 rpm and the vial swirled for no longer than 30 minutes.
Once reconstitution is complete, the solution should be opalescent and colorless to pale yellow, and without particles. Small air bubbles, however, are expected and acceptable. DilutionInstructions
Dextrose intravenous solutions are incompatible with BENLYSTA. BENLYSTA should only be diluted in 0.9% Sodium Chloride Injection, USP. Dilute the reconstituted product to 250 mL in 0.9% Sodium Chloride Injection, USP (normal saline) for intravenous infusion. From a 250-mL infusion bag or bottle of normal saline, withdraw and discard a volume equal to the volume of the reconstituted solution of BENLYSTA required for the patient’s dose. Then add the required volume of the reconstituted solution of BENLYSTA into the infusion bag or bottle. Gently invert the bag or bottle to mix the solution. Any unused solution in the vials must be discarded.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard the solution if any particulate matter or discoloration is observed.
The reconstituted solution of BENLYSTA, if not used immediately, should be stored protected from direct sunlight and refrigerated at 2° to 8°C (36° to 46°F). Solutions of BENLYSTA diluted in normal saline may be stored at 2° to 8°C (36° to 46°F) or room temperature. The total time from reconstitution of BENLYSTA to completion of infusion should not exceed 8 hours.
No incompatibilities between BENLYSTA and polyvinylchloride or polyolefin bags have been observed.

2.42.4 Administration Instructions

The diluted solution of BENLYSTA should be administered by intravenous infusion only, over a period of 1 hour.
BENLYSTA should be administered by healthcare providers prepared to manage anaphylaxis. [seeWarnings and Precautions (5.4)]
BENLYSTA should not be infused concomitantly in the same intravenous line with other agents. No physical or biochemical compatibility studies have been conducted to eva luate the coadministration of BENLYSTA with other agents.

33 DOSAGE FORMS AND STRENGTHS

Single-use vials of belimumab lyophilized powder for injection:

120 mg per vial
400 mg per vial

44 CONTRAINDICATIONS

BENLYSTA is contraindicated in patients who have had anaphylaxis with belimumab.

55 WARNINGS AND PRECAUTIONS

5.15.1 Mortality

There were more deaths reported with BENLYSTA than with placebo during the controlled period of the clinical trials. Out of 2133 patients in 3 clinical trials, a total of 14 deaths occurred during the placebo-controlled, double-blind treatment periods: 3/675 (0.4%), 5/673 (0.7%), 0/111 (0%), and 6/674 (0.9%) deaths in the placebo, BENLYSTA 1 mg/kg, BENLYSTA 4 mg/kg, and BENLYSTA 10 mg/kg groups, respectively. No single cause of death predominated. Etiologies included infection, cardiovascular disease and suicide.

5.25.2 Serious Infections

Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents, including BENLYSTA. Physicians should exercise caution when considering the use of BENLYSTA in patients with chronic infections. Patients receiving any therapy for chronic infection should not begin therapy with BENLYSTA. Consider interrupting BENLYSTA therapy in patients who develop a new infection while undergoing treatment with BENLYSTA and monitor these patients closely.

In the controlled clinical trials, the overall incidence of infections was 71% in patients treated with BENLYSTA compared with 67% in patients who received placebo. The most frequent infections (>5% of patients receiving BENLYSTA) were upper respiratory tract infection, urinary tract infection, nasopharyngitis, sinusitis, bronchitis, and influenza. Serious infections occurred in 6.0% of patients treated with BENLYSTA and in 5.2% of patients who received placebo. The most frequent serious infections included pneumonia, urinary tract infection, cellulitis, and bronchitis. Infections leading to discontinuation of treatment occurred in 0.7% of patients receiving BENLYSTA and 1.0% of patients receiving placebo. Infections resulting in death occurred in 0.3% (4/1458) of patients treated with BENLYSTA and in 0.1% (1/675) of patients receiving placebo.

5.35.3 Malignancy

The impact of treatment with BENLYSTA on the development of malignancies is not known. In the controlled clinical trials, malignancies (including non-melanoma skin cancers) were reported in 0.4% of patients receiving BENLYSTA and 0.4% of patients receiving placebo. In the controlled clinical trials, malignancies, excluding non-melanoma skin cancers, were observed in 0.2% (3/1458) and 0.3% (2/675) of patients receiving BENLYSTA and placebo, respectively. As with other immunomodulating agents, the mechanism of action of BENLYSTA could increase the risk for the development of malignancies.

5.45.4 Hypersensitivity Reactions, Including Anaphylaxis

Hypersensitivity reactions, including anaphylaxis and death, have been reported in association with BENLYSTA. Delay in the onset of acute hypersensitivity reactions has been observed. Limited data suggest that patients with a history of multiple drug allergies or significant hypersensitivity may be at increased risk. In the controlled clinical trials, hypersensitivity reactions (occurring on the same day of infusion) were reported in 13% (191/1458) of patients receiving BENLYSTA and 11% (76/675) of patients receiving placebo. Anaphylaxis was observed in 0.6% (9/1458) of patients receiving BENLYSTA and 0.4% (3/675) of patients receiving placebo. Manifestations included hypotension, angioedema, urticaria or other rash, pruritus, and dyspnea. Due to overlap in signs and symptoms, it was not possible to distinguish between hypersensitivity reactions and infusion reactions in all cases [see Warnings and Precautions (5.5)]. Some patients (13%) received premedication, which may have mitigated or masked a hypersensitivity response; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of hypersensitivity reactions.

BENLYSTA should be administered by healthcare providers prepared to manage anaphylaxis. In the event of a serious reaction, administration of BENLYSTA must be discontinued immediately and appropriate medical therapy administered. Patients should be monitored during and for an appropriate period of time after administration of BENLYSTA. Patients should be informed of the signs and symptoms of a hypersensitivity reaction and instructed to seek immediate medical care should a reaction occur.

5.55.5 Infusion Reactions

In the controlled clinical trials, adverse events associated with the infusion (occurring on the same day of the infusion) were reported in 17% (251/1458) of patients receiving BENLYSTA and 15% (99/675) of patients receiving placebo. Serious infusion reactions (excluding hypersensitivity reactions) were reported in 0.5% of patients receiving BENLYSTA and 0.4% of patients receiving placebo and included bradycardia, myalgia, headache, rash, urticaria, and hypotension. The most common infusion reactions (≥ 3% of patients receiving BENLYSTA) were headache, nausea, and skin reactions. Due to overlap in signs and symptoms, it was not possible to distinguish between hypersensitivity reactions and infusion reactions in all cases [see Warnings and Precautions (5.4)]. Some patients (13%) received premedication, which may have mitigated or masked an infusion reaction; however there is insufficient evidence to determine whether premedication diminishes the frequency or severity of infusion reactions [seeAdverse Reactions (6.1)].

BENLYSTA should be administered by healthcare providers prepared to manage infusion reactions. The infusion rate may be slowed or interrupted if the patient develops an infusion reaction. Healthcare providers should be aware of the risk of hypersensitivity reactions, which may present as infusion reactions, and monitor patients closely.

5.65.6 Depression

In the controlled clinical trials, psychiatric events were reported more frequently with BENLYSTA (16%) than with placebo (12%), related primarily to depression-related events (6.3% BENLYSTA and 4.7% placebo), insomnia (6.0% BENLYSTA and 5.3% placebo), and anxiety (3.9% BENLYSTA and 2.8% placebo). Serious psychiatric events were reported in 0.8% of patients receiving BENLYSTA (0.6% and 1.2% with 1 and 10 mg/kg, respectively) and 0.4% of patients receiving placebo. Serious depression was reported in 0.4% (6/1458) of patients receiving BENLYSTA and 0.1% (1/675) of patients receiving placebo. Two suicides (0.1%) were reported in patients receiving BENLYSTA. The majority of patients who reported serious depression or suicidal behavior had a history of depression or other serious psychiatric disorders and most were receiving psychoactive medications. It is unknown if BENLYSTA treatment is associated with increased risk for these events.

Patients receiving BENLYSTA should be instructed to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts, or other mood changes.

5.75.7 Immunization

Live vaccines should not be given for 30 days before or concurrently with BENLYSTA as clinical safety has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving BENLYSTA or the effect of BENLYSTA on new immunizations. Because of its mechanism of action, BENLYSTA may interfere with the response to immunizations.

5.85.8 Concomitant Use with Other Biologic Therapies or Intravenous Cyclophosphamide

BENLYSTA has not been studied in combination with other biologic therapies, including B-cell targeted therapies, or intravenous cyclophosphamide. Therefore, use of BENLYSTA is not recommended in combination with biologic therapies or intravenous cyclophosphamide.

66 ADVERSE REACTIONS

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The following have been observed with BENLYSTA and are discussed in detail in the Warnings and Precautions section: