英文药名：BENLYSTA(belimumab powder solution infusion)

中文药名：贝利单抗冻干粉剂

生产厂家：葛兰素史克制药公司
药品介绍
注射用BENLYSTA(belimumab)-56年来首种治疗红斑狼疮上市新药
初次批准：2011
适应证和用途
BENLYSTA是一种B-淋巴细胞刺激剂(BLyS)-特异性抑制剂适用于治疗正在接受标准治疗的有活动性，自身抗体-阳性，全身性红斑狼疮成年患者。
使用限制：尚未在有严重活动性狼疮肾炎或严重活动性中枢神经系统狼患者疮中评价BENLYSTA的疗效。尚未研究BENLYSTA与其它生物制品或静脉环磷酰胺联用。不建议在这些情况中使用BENLYSTA。
剂量和给药方法
（1）推荐给药方案是对头3剂间隔2-周10 mg/kg和其后间隔4-周。配制，稀释和只作为静脉输注在1小时期间给药。
（2）为预防输注反应和超敏性反应考虑预防给药。
剂型和规格
单次使用belimumab冻干粉小瓶：
（1）每小瓶120 mg
（2）每小瓶400 mg
禁忌证
既往对belimumab过敏反应。
警告和注意事项
（1）死亡率：临床试验的对照阶段期间用BENLYSTA比用安慰剂报道更多死亡。
（2）严重感染：在接受免疫抑制剂，包括BENLYSTA患者中曾报道严重和有时致命性感染。有慢性感染患者中慎用。BENLYSTA治疗期间如患者发生新感染考虑中断BENLYSTA治疗。
（3）超敏性反应，包括过敏反应：曾报道严重反应。应由准备处理过敏反应保健提供者给予BENLYSTA。给予BENLYSTA期间和后适当时间监视患者。
（4）抑郁：在BENLYSTA研究中曾报道抑郁和自杀倾向。应指导患者如经受新或恶化的抑郁，自杀想法或其它情绪变化联系他们的保健提供者。
（5）免疫接种：不应同时给予活疫苗与BENLYSTA。
不良反应
在临床试验中常见不良反应(≥5%)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。
在特殊人群中使用
（1）妊娠：可得到注册。

葛兰素史克新型狼疮药Benlysta获英国NICE批准
英国制药巨头葛兰素史克（GSK）新型狼疮药Benlysta（belimumab，贝利木单抗）近日获得英国医疗成本监管机构——英国国家卫生与临床优化研究所（NICE）支持，用于英格兰和威尔士国家卫生服务（NHS）系统。NICE已发布最终指南，推荐Benlysta用于系统性红斑狼疮（SLE）患者的治疗。
Benlytsa（贝利木单抗）是近50多年来获批用于治疗红斑狼疮的首个新药，于2011年获得美国和欧盟批准，用于自身抗体阳性（autoantibody-positive）的系统性红斑狼疮（SLE）成年患者的治疗。在此之前，美国FDA仅于1948年批准阿司匹林、1955年批准羟基氯喹和皮质激素治疗狼疮，因此Benlytsa的上市具有划时代的意义。
然而，英国NICE却认为Benlytsa价格过于昂贵，不具有成本效益，因此迟迟未批准该药用于国家卫生服务（NHS）系统。据悉，Benlysta此次获得NICE肯定，是由于葛兰素史克与NHS达成了一定的折扣协议，同时还提供了相关数据消除了Benlysta在疗效方面的一些疑问。
Benlysta是首个B淋巴细胞刺激因子（B lymphocyte stimulator，BLyS）特异性抑制剂，能阻断可溶性BLyS（一种B细胞生存因子）与B细胞上的BLyS受体的结合。Benlysta与B细胞不直接结合，但通过与BLyS结合，Benlysta可抑制B细胞(包括自身反应性B细胞)的生存、减少B细胞向制造免疫球蛋白的浆细胞的分化。Benlysta能够减少导致狼疮患者病情加重的异常B淋巴细胞的数量，这些异常的B淋巴细胞会导致免疫系统产生细胞错误攻击血管和自身其他健康组织，从而引起狼疮和其他免疫系统疾病。
系统性红斑狼疮是一种慢性自身免疫疾病，如果病情得不到控制，将会导致严重的症状，包括长期的器官损伤，甚至过早死亡，该病同时会对患者的身心健康造成巨大影响。据估计，目前英国约有20000名红斑狼疮患者，许多晚期患者采用现有治疗手段已无法控制病情，因此亟需新的治疗药物，Benlysta将为这类患者提供一种重要的新治疗选择。
Benlysta 120 mg and 400 mg powder for concentrate for solution for infusion
1. Name of the medicinal product
Benlysta® ▼ 120 mg powder for concentrate for solution for infusion.
Benlysta® ▼400 mg powder for concentrate for solution for infusion.
2. Qualitative and quantitative composition
Each vial contains 120 mg of belimumab. After reconstitution, the solution contains 80 mg belimumab per ml.
Each vial contains 400 mg of belimumab. After reconstitution, the solution contains 80 mg belimumab per ml.
Belimumab is a human, IgG1λ monoclonal antibody, produced in a mammalian cell line (NS0) by recombinant DNA technology.
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Powder for concentrate for solution for infusion.
White to off-white powder.
4. Clinical particulars
4.1 Therapeutic indications
Benlysta is indicated as add-on therapy in adult patients with active, autoantibody-positive systemic lupus erythematosus (SLE) with a high degree of disease activity (e.g positive anti-dsDNA and low complement) despite standard therapy (see section 5.1).
4.2 Posology and method of administration
Benlysta treatment should be initiated and supervised by a qualified physician experienced in the diagnosis and treatment of SLE. Benlysta infusions should be administered by a qualified healthcare professional trained to give infusion therapy. Administration of Benlysta may result in severe or life-threatening hypersensitivity reactions and infusion reactions. Patients have been reported to develop symptoms of acute hypersensitivity several hours after the infusion has been administered. Recurrence of clinically significant reactions after initial appropriate treatment of symptoms has also been observed (see section 4.4 and 4.8). Therefore, Benlysta should be administered in an environment where resources for managing such reactions are immediately available. Patients should remain under clinical supervision for a prolonged period of time (for several hours), following at least the first 2 infusions, taking into account the possibility of a late onset reaction.
Patients treated with Benlysta should be made aware of the potential risk of severe or life-threatening hypersensitivity and the potential for delayed onset or recurrence of symptoms. The package leaflet should be provided to the patient each time Benlysta is administered (see section 4.4).
There are no or insufficient data available on the effects of Benlysta in patients with severe active lupus nephritis or severe active central nervous system lupus. Therefore, Benlysta cannot be recommended to treat these conditions (see section 4.4).
Posology
Premedication including an antihistamine, with or without an antipyretic, may be administered before the infusion of Benlysta (see section 4.4).
The recommended dose regimen is 10 mg/kg Benlysta on Days 0, 14 and 28, and at 4-week intervals thereafter. The patient's condition should be evaluated continuously. Discontinuation of treatment with Benlysta should be considered if there is no improvement in disease control after 6 months of treatment.
Special populations
Older people (>65 years)
The efficacy and safety of Benlysta in the elderly has not been established. Data on patients >65 years are limited to <1.6% of the studied population. Therefore, the use of Benlysta in elderly patients is not recommended unless the benefits are expected to outweigh the risks. In case administration of Benlysta to elderly patients is deemed necessary, dose adjustment is not required (see section 5.2).
Renal impairment
Belimumab has been studied in a limited number of SLE patients with renal impairment.
On the basis of the available information, dose adjustment is not required in patients with mild, moderate or severe renal impairment. Caution is however recommended in patients with severe renal impairment due to the lack of data (see section 5.2).
Hepatic impairment
No specific studies with Benlysta have been conducted in patients with hepatic impairment. Patients with hepatic impairment are unlikely to require dose adjustment (see section 5.2).
Paediatric population
The safety and efficacy of Benlysta in children (less than 18 years of age) has not been established. No data are available.
Method of administration
Benlysta is administered intravenously by infusion, and must be reconstituted and diluted before administration. For instructions on reconstitution, dilution, and storage of the medicinal product before administration, see section 6.6.
Benlysta should be infused over a 1-hour period.
Benlysta must not be administered as an intravenous bolus.
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 potentially life-threatening adverse reaction (see sections 4.4 and 4.8).
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
Benlysta has not been studied in the following patient groups, and is not recommended in:
• severe active central nervous system lupus
• severe active lupus nephritis (see section 5.1)
• HIV
• a history of, or current, hepatitis B or C
• hypogammaglobulinaemia (IgG <400 mg/dl) or IgA deficiency (IgA <10 mg/dl)
• a history of major organ transplant or hematopoietic stem /cell /marrow transplant or renal transplant.
Concomitant use with B cell targeted therapy or cyclophosphamide
Benlysta has not been studied in combination with other B cell targeted therapy or intravenous cyclophosphamide. Caution should be exercised if Benlysta is co-administered with other B cell targeted therapy or cyclophosphamide.
Infusion reactions and hypersensitivity
Administration of Benlysta may result in hypersensitivity reactions and infusion reactions which can be severe, and can be fatal. In the event of a severe reaction, Benlysta administration must be interrupted and appropriate medical therapy administered (see section 4.2). The risk of hypersensitivity reactions is greatest with the first two infusions; however the risk should be considered for every infusion administered. Patients with a history of multiple drug allergies or significant hypersensitivity may be at increased risk.
Premedication including an antihistamine, with or without an antipyretic, may be administered before the infusion of Benlysta. There is insufficient evidence to determine whether premedication diminishes the frequency or severity of infusion reactions.
In clinical studies, serious infusion and hypersensitivity reactions affected approximately 0.9% of patients, and included anaphylactic reaction, bradycardia, hypotension, angioedema, and dyspnoea. Infusion reactions occurred more frequently during the first two infusions and tended to decrease with subsequent infusions (see section 4.8). Patients have been reported to develop symptoms of acute hypersensitivity several hours after the infusion has been administered. Recurrence of clinically significant reactions after initial appropriate treatment of symptoms has also been observed (see section 4.2 and 4.8). Therefore, Benlysta should be administered in an environment where resources for managing such reactions are immediately available. Patients should remain under clinical supervision for a prolonged period of time (for several hours), following at least the first 2 infusions, taking into account the possibility of a late onset reaction. Patients should be advised that hypersensitivity reactions are possible on the day of, or the day after infusion, and be informed of potential signs and symptoms and the possibility of recurrence. Patients should be instructed to seek immediate medical attention if they experience any of these symptoms. The package leaflet should be provided to the patient each time Benlysta is administered (see section 4.2).
Delayed-type, non-acute hypersensitivity reactions have also been observed and included symptoms such as rash, nausea, fatigue, myalgia, headache, and facial oedema.
Infections
The mechanism of action of Benlysta could increase the potential risk for the development of infections, including opportunistic infections. Physicians should exercise caution when considering the use of Benlysta in patients with chronic infections or a history of recurrent infection. Patients receiving any therapy for chronic infection should not begin therapy with Benlysta. Patients who develop an infection while undergoing treatment with Benlysta should be monitored closely. The risk of using Benlysta in patients with active or latent tuberculosis is unknown.
Progressive multifocal leukoencephalopathy
Progressive multifocal leukoencephalopathy (PML) has been reported with Benlysta treatment for SLE. Physicians should be particularly alert to symptoms suggestive of PML that patients may not notice (e.g., cognitive, neurological or psychiatric symptoms or signs). Patients should be monitored for any of these new or worsening symptoms or signs, and if such symptoms/signs occur, referral to a neurologist and appropriate diagnostic measures for PML should be considered. If PML is suspected, further dosing must be suspended until PML has been excluded.
Immunisation
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. Because of its mechanism of action, belimumab may interfere with the response to immunisations. The efficacy of concurrent vaccination in patients receiving Benlysta is not known. Limited data suggest that Benlysta does not significantly affect the ability to maintain a protective immune response to immunisations received prior to administration of Benlysta. In a substudy, a small group of patients who had previously received either tetanus, pneumococcal or influenza vaccinations were found to maintain protective titres after treatment with Benlysta. There are insufficient data to draw conclusions regarding the ability of subjects receiving Benlysta to mount protective responses to vaccines.
Malignancies and lymphoproliferative disorders
Immunomodulatory medicinal products, including belimumab, may increase the risk of malignancy. Caution should be exercised when considering belimumab therapy for patients with a history of malignancy or when considering continuing treatment in patients who develop malignancy. Patients with malignant neoplasm within the last 5 years have not been studied, with the exception of those with basal or squamous cell cancers of the skin, or cancer of the uterine cervix, that has been fully excised or adequately treated.
4.5 Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed.
4.6 Fertility, pregnancy and lactation
Women of childbearing potential/Contraception in males and females
Women of child-bearing potential must use effective contraception during Benlysta treatment and for at least 4 months after the last treatment.
Pregnancy
There are a limited amount of data from the use of Benlysta in pregnant women. No formal studies have been conducted. Besides an expected pharmacological effect i.e. reduction of B cells, animal studies in monkeys do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).
Benlysta should not be used during pregnancy unless clearly necessary.
Breast-feeding
It is unknown whether Benlysta is excreted in human milk or is absorbed systemically after ingestion. However, belimumab was detected in the milk from female monkeys administered 150 mg/kg every 2 weeks.
Because maternal antibodies (IgG) are excreted in breast milk, it is recommended that a decision should be made whether to discontinue breast-feeding or to discontinue Benlysta therapy, taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.
Fertility
There are no data on the effects of Benlysta on human fertility. Effects on male and female fertility have not been formally evaluated in animal studies (see section 5.3).
4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed. No detrimental effects on such activities are predicted from the pharmacology of Benlysta. The clinical status of the subject and the adverse reaction profile of Benlysta should be borne in mind when considering the patient's ability to perform tasks that require judgement, motor or cognitive skills.
4.8 Undesirable effects
Summary of the safety profile
The safety of Benlysta in patients with SLE has been evaluated in 3 placebo-controlled studies.
The data described below reflect exposure to Benlysta 10 mg/kg in 674 patients with SLE, including 472 exposed for at least 52 weeks. The safety data presented include data beyond Week 52 in some patients.
Data from postmarketing reports are also included.
Patients received Benlysta 10 mg/kg intravenously over a 1-hour period on Days 0, 14, 28, and then every 28 days for 52 weeks.
The majority of patients were also receiving one or more of the following concomitant treatments for SLE: corticosteroids, immunomodulatory medicinal products, anti-malarials, non-steroidal anti-inflammatory medicinal products.
Adverse reactions were reported in 93% of Benlysta-treated patients and 92% of placebo-treated patients. The most frequently reported adverse reactions (≥10% of patient with SLE treated with Benlysta plus standard of care and at a rate ≥1% greater than placebo) were nausea, diarrhoea, and pyrexia. The proportion of patients who discontinued treatment due to adverse reactions was 7% for both Benlysta-treated and placebo-treated patients.
Tabulated list of adverse reactions
Adverse reactions are listed below by MedDRA system organ class and by frequency. The frequency categories used are:
Very common
Common
Uncommon
Rare
 > 1/10

≥1/100 to <1/10

≥1/1,000 to <1/100

>1/10,000 to <1/1000
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

System organ class	Frequency	Adverse reaction(s)
Infections and infestations	Very Common	Bacterial Infections, e.g. bronchitis, cystitis
	Common	Gastroenteritis viral, pharyngitis, nasopharyngitis
Blood and lymphatic system disorders	Common	Leucopenia
Immune system disorders	Common	Hypersensitivity reactions*
	Uncommon	Anaphylactic reaction, angioedema
	Rare	Delayed-type, non-acute hypersensitivity reactions
Psychiatric disorders	Common	Depression, insomnia
Nervous system disorders	Common	Migraine
Gastrointestinal disorders	Very common	Diarrhoea, nausea
Skin and subcutaneous tissue disorders	Uncommon	Urticaria, rash
Musculoskeletal and connective tissue disorders	Common	Pain in extremity
General disorders and administration site conditions	Common	Infusion-related reactions*, pyrexia

*'Hypersensitivity reactions' covers a group of terms, including anaphylaxis, and can manifest as a range of symptoms including hypotension, angioedema, urticaria or other rash, pruritus, and dyspnoea. 'Infusion-related reactions' covers a group of terms and can manifest as a range of symptoms including bradycardia, myalgia, headache, rash, urticaria, pyrexia, hypotension, hypertension, dizziness, and arthralgia. Due to overlap in signs and symptoms, it is not possible to distinguish between hypersensitivity reactions and infusion reactions in all cases.
Description of selected adverse reactions
Infusion reactions and hypersensitivity: The incidence of infusion reactions and hypersensitivity reactions occurring during or on the same day as an infusion was 17% in the group receiving Benlysta and 15% in the group receiving placebo, with 1% and 0.3%, respectively, requiring permanent treatment discontinuation.
These reactions were generally observed on the day of infusion, but acute hypersensitivity reactions may also occur on the day after dosing. Patients with a history of multiple drug allergies or significant hypersensitivity reactions may be at increased risk.
Infections: The overall incidence of infections was 70% in the group receiving Benlysta and 67% in the group receiving placebo. Infections occurring in at least 3% of Benlysta patients and at least 1% more frequently than patients receiving placebo were nasopharyngitis, bronchitis, pharyngitis, cystitis, and gastroenteritis viral. Serious infections occurred in 5% of patients receiving Benlysta or placebo. Infections leading to discontinuation of treatment occurred in 0.6% of patients receiving Benlysta and 1% of patients receiving placebo. Opportunistic infections have been reported in patients treated with Benlysta.
Leucopenia: The incidence of leucopenia reported as an adverse event was 4% in the group receiving Benlysta and 2% in the group receiving placebo.
Psychiatric disorders: Insomnia occurred in 7% of the group receiving Benlysta and 5% of the group receiving placebo. Depression was reported in 5% and 4% of the groups receiving Benlysta and placebo, respectively.
Gastrointestinal disorders: Obese patients (BMI >30 kg/m2) treated with Benlysta reported higher rates of nausea, vomiting and diarrhoea relative to placebo, and compared with normal-weight patients (BMI ≥18.5 to ≤30 kg/m2). None of these gastrointestinal events in obese patients were serious.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
4.9 Overdose
There is no clinical experience with overdose of Benlysta.
Two doses up to 20 mg/kg administered 21 days apart by intravenous infusion have been given to humans with no increase in incidence or severity of adverse reactions compared with doses of 1, 4, or 10 mg/kg.
In the case of inadvertent overdose, patients should be carefully observed and supportive care administered, as appropriate.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Selective immunosuppressants, ATC code: L04AA26
Mechanism of action
Benlysta is a human IgG1λ monoclonal antibody specific for soluble human B Lymphocyte Stimulator protein (BLyS, also referred to as BAFF and TNFSF13B). Benlysta blocks the binding of soluble BLyS, a B cell survival factor, to its receptors on B cells. Benlysta does not bind B cells directly, but by binding BLyS, Benlysta inhibits the survival of B cells, including autoreactive B cells, and reduces the differentiation of B cells into immunoglobulin-producing plasma cells.
BLyS levels are elevated in patients with SLE and other autoimmune diseases. There is an association between plasma BLyS levels and SLE disease activity. The relative contribution of BLyS levels to the pathophysiology of SLE is not fully understood.
Pharmacodynamic effects
Changes in biomarkers were seen in clinical trials. In patients with hypergammaglobulinemia, normalization of IgG levels was observed by Week 52 in 49% and 20% of patients receiving Benlysta and placebo, respectively.
In patients with anti-dsDNA antibodies, 16% of patients treated with Benlysta converted to anti-dsDNA negative compared with 7% of the patients receiving placebo by Week 52.
In patients with low complement levels, normalization of C3 and C4 was observed by Week 52 in 38% and 44% of patients receiving Benlysta and in 17% and 19% of patients receiving placebo.
Of the anti-phospholipid antibodies, only anti-cardiolipin antibody was measured. For anti-cardiolipin IgA antibody a 37% reduction at Week 52 was seen (p=0.0003), for anti-cardiolipin IgG antibody a 26% reduction at Week 52 was seen (p=0.0324) and for anti-cardiolipin IgM a 25% reduction was seen (p=NS, 0.46).
In a long-term extension study, B cells (including naïve, activated, plasma cells and the SLE B cell subset) and IgG levels were followed for up to 172 weeks with ongoing belimumab treatment. A substantial and sustained decrease in various B cell subsets was observed leading to a 70% to 90% median reduction in naïve B cells, activated B cells and plasmacytoid cells, and up to 60% median reduction in plasma cells after 3 years of treatment. Over three years, a 20% to 30% median reduction in IgG levels was observed, with 0.5% of subjects experiencing a decrease in IgG levels to below 400 mg/dL. The impact of long-term B cell decrease on efficacy and safety has not yet been determined.
Immunogenicity
Assay sensitivity for neutralising antibodies and non-specific anti-drug antibody (ADA) is limited by the presence of active drug in the collected samples. The true occurrence of neutralising antibodies and non-specific anti-drug antibody in the study population is therefore not known.
In the two Phase III studies, 4 out of 563 (0.7%) patients in the 10 mg/kg group and 27 out of 559 (4.8%) patients in the 1 mg/kg group tested positive for persistent presence of anti-belimumab antibodies.
Among persistent-positive subjects in the Phase III studies, 1/10 (10%), 2/27 (7%) and 1/4 (25%) subjects in the placebo, 1 mg/kg and 10 mg/kg groups, respectively, experienced infusion reactions on a dosing day; these infusion reactions were all non-serious and mild to moderate in severity. Few patients with ADA reported serious/severe AEs. The rates of infusion reactions among persistent-positive subjects were comparable to the rates for ADA negative patients of 75/552 (14%), 78/523 (15%), and 83/559 (15%) in the placebo, 1 mg/kg and 10 mg/kg groups, respectively.
Clinical efficacy and safety
The efficacy of Benlysta was evaluated in 2 randomized, double-blind, placebo-controlled studies in 1,684 patients with a clinical diagnosis of SLE according to the American College of Rheumatology classification criteria. Patients had active SLE disease, defined as a SELENA-SLEDAI (SELENA=Safety of Estrogens in Systemic Lupus Erythematosus National Assessment; SLEDAI=Systemic Lupus Erythematosus Disease Activity Index) score ≥6 and positive anti-nuclear antibody (ANA) test results (ANA titre ≥1:80 and/or a positive anti-dsDNA [≥30 units/ml]) at screening. Patients were on a stable SLE treatment regimen consisting of (alone or in combination): corticosteroids, anti-malarials, NSAIDs or other immunosuppressives. The two studies were similar in design except that BLISS-76 was a 76-week study and BLISS-52 was a 52-week study. In both studies the primary efficacy endpoint was evaluated at 52 weeks.
Patients who had severe active lupus nephritis and patients who had severe active central nervous system (CNS) lupus were excluded.
BLISS-76 was conducted primarily in North America and Western Europe. Background medicinal products included corticosteroids (76%; >7.5 mg/day 46%), immunosuppressives (56%), and anti-malarials (63%).
BLISS-52 was conducted in South America, Eastern Europe, Asia, and Australia. Background medicinal products included corticosteroids (96%; >7.5 mg/day 69%), immunosuppressives (42%), and anti-malarials (67%).
At baseline 52% of patients had high disease activity (SELENA SLEDAI score >10), 59% of patients had mucocutaneous, 60% had musculoskeletal, 16% had haematological, 11% had renal and 9% had vascular organ domain involvement (BILAG A or B at baseline).
The primary efficacy endpoint was a composite endpoint (SLE Responder Index) that defined response as meeting each of the following criteria at Week 52 compared with baseline:
• ≥ 4-point reduction in the SELENA-SLEDAI score, and
• no new British Isles Lupus Assessment Group (BILAG) A organ domain score or 2 new BILAG B organ domain scores, and
• no worsening (>0.30 point increase) in Physician's Global Assessment score (PGA)
The SLE Responder Index measures improvement in SLE disease activity, without worsening in any organ system, or in the patient's overall condition.
Table 1: Response Rate at Week 52

Response	BLISS-76		BLISS-52		BLISS-76 and BLISS-52 Pooled
	Placebo* (n=275)	Benlysta 10 mg/kg* (n=273)	Placebo* (n=287)	Benlysta 10 mg/kg* (n=290)	Placebo* (n=562)	Benlysta 10 mg/kg* (n=563)
SLE Responder Index Observed difference vs placebo Odds ratio (95% CI) vs placebo	33.8%	43.2% (p=0.021) 9.4% 1.52 (1.07, 2.15)	43.6%	57.6% (p=0.0006) 14.0% 1.83 (1.30,2.59)	38.8%	50.6% (p<0.0001) 11.8% 1.68 (1.32,2.15)
Components of SLE Responder Index
Percent of patients with reduction in SELENA-SLEDAI ≥4	35.6%	46.9% (p=0.006	46.0%	58.3% (p= 0.0024)	40.9%	52.8% (p<0.0001)
Percent of patients with no worsening by BILAG index	65.1%	69.2% (p=0.32)	73.2%	81.4% (p=0.018)	69.2%	75.5% (p=0.019)
Percent of patients with no worsening by PGA	62.9%	69.2% (p=0.13)	69.3%	79.7% (p=0.0048)	66.2%	74.6% (p=0.0017)

* plus standard therapy/standard of care
In a pooled analysis of the two studies, the percentage of patients receiving >7.5 mg/day prednisone (or equivalent) at baseline, whose average corticosteroid dose was reduced by at least 25% to a dose equivalent to prednisone ≤7.5 mg/day during Weeks 40 through 52, was 17.9% in the group receiving Benlysta and 12.3% in the group receiving placebo (p=0.0451).
Flares in SLE were defined by the modified SELENA SLEDAI SLE Flare Index. The median time to the first flare was delayed in the pooled group receiving belimumab compared to the group receiving placebo (110 vs 84 days, hazard ratio=0.84, p=0.012). Severe flares were observed in 15.6% of the Benlysta group compared to 23.7% of the placebo group over the 52 weeks of observation (observed treatment difference = -8.1%; hazard ratio=0.64, p=0.0011).
Benlysta demonstrated improvement in fatigue compared with placebo measured by the FACIT-Fatigue scale in the pooled analysis. The mean change of score at Week 52 from baseline is significantly greater with Benlysta compared to placebo (4.70 vs 2.46, p=0.0006).
Univariate and multivariate analysis of the primary endpoint in pre-specified subgroups demonstrated that the greatest benefit was observed in patients with higher disease activity including patients with SELENA SLEDAI scores ≥ 10, patients requiring steroids to control their disease, and patients with low complement levels.
Post-hoc analysis has identified high responding subgroups such as those patients with low complement and positive anti-dsDNA at baseline, see Table 2. Of these patients, 64.5% had SELENA SLEDAI scores ≥ 10 at baseline.
Table 2: Patients with low complement and positive anti-dsDNA at baseline

Subgroup	Anti-dsDNA positive AND low complement
BLISS-76 and BLISS-52 pooled data	Placebo (n=287)	Benlysta 10 mg/kg (n=305)
SRI response rate at Week 52 (%) Observed treatment difference vs placebo (%)	31.7	51.5 (p<0.0001) 19.8
SRI response rate (excluding complement and anti-dsDNA changes) at Week 52 (%) Observed treatment difference vs placebo (%)	28.9	46.2 (p<0.0001) 17.3
Severe flares over 52 weeks Patients experiencing a severe flare (%) Observed treatment difference vs placebo (%) Time to severe flare [Hazard ratio (95% CI)]	29.6	19.0 10.6 0.61 (0.44, 0.85) (p=0.0038)
Prednisone reduction by ≥25% from baseline to ≤7.5 mg/day during Weeks 40 through 52* (%)   Observed treatment difference vs placebo (%)	(n=173) 12.1	(n=195) 18.5 (p=0.0964) 6.3
FACIT-fatigue score improvement from baseline at Week-52 (mean) Observed treatment difference vs placebo (mean difference)	1.99	4.21 (p=0.0048) 2.21
BLISS-76 Study only	Placebo (n=131)	Benlysta 10 mg/kg (n=134)
SRI response rate at Week-76 (%) Observed treatment difference vs placebo (%)	27.5	39.6 (p=0.0160) 12.1

* Among patients with baseline prednisone dose >7.5 mg/day
Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with Benlysta in one or more subsets of the paediatric population in SLE (see section 4.2 for information on paediatric use).
Age and race
There were too few patients over 65 years of age, or black/African American patients enrolled in the controlled clinical trials to draw meaningful conclusions about the effects of age or race on clinical outcomes.
5.2 Pharmacokinetic properties
The pharmacokinetic parameters quoted below are based on population parameter estimates for the 563 patients who received Benlysta 10 mg/kg in the two Phase III studies.
Absorption
Benlysta is administered by intravenous infusion. Maximum serum concentrations of belimumab were generally observed at, or shortly after, the end of the infusion. The maximum serum concentration was 313 µg/ml (range: 173-573 µg/ml) based on simulating the concentration time profile using the typical parameter values of the population pharmacokinetic model.
Distribution
Belimumab distributed to tissues with an overall volume of distribution of 5.29 litres.
Biotransformation
Belimumab is a protein for which the expected metabolic pathway is degradation to small peptides and individual amino acids by widely distributed proteolytic enzymes. Classical biotransformation studies have not been conducted.
Elimination
Serum belimumab concentrations declined in a bi-exponential manner, with a distribution half-life of 1.75 days and terminal half-life 19.4 days. The systemic clearance was 215 ml/day (range: 69-622 ml/day).
Paediatric population: No pharmacokinetic data are available in paediatric patients.
Older people (older than or equal to 65 years of age): Benlysta has been studied in a limited number of elderly patients. Within the overall SLE intravenous study population, age did not affect belimumab exposure in the population pharmacokinetic analysis. However, given the small number of subjects 65 years or older, an effect of age cannot be ruled out conclusively.
Renal impairment: No specific studies have been conducted to examine the effects of renal impairment on the pharmacokinetics of Benlysta. During clinical development Benlysta was studied in patients with SLE and renal impairment (261 subjects with moderate renal impairment, creatinine clearance ≥30 and <60 ml/min; 14 subjects with severe renal impairment, creatinine clearance ≥15 and <30 ml/min). The reduction in systemic clearance estimated by population PK modelling for patients at the midpoints of the renal impairment categories relative to patients with median creatinine clearance in the PK population (79.9 ml/min) were 1.4% for mild (75 ml/min), 11.7% for moderate (45 ml/min) and 24.0% for severe (22.5 ml/min) renal impairment. Although proteinuria (> 2 g/day) increased belimumab clearance and decreases in creatinine clearance decreased belimumab clearance, these effects were within the expected range of variability. Therefore, no dose adjustment is recommended for patients with renal impairment.
Hepatic impairment: No specific studies have been conducted to examine the effects of hepatic impairment on the pharmacokinetics of belimumab. IgG1 molecules such as belimumab are catabolised by widely distributed proteolytic enzymes, which are not restricted to hepatic tissue and changes in hepatic function are unlikely to have any effect on the elimination of belimumab.
Body weight/BMI: Weight-normalised belimumab dosing leads to decreased exposure for underweight subjects (BMI <18.5) and to increased exposure for obese subjects (BMI >30). BMI-dependent changes in exposure did not lead to corresponding changes in efficacy. Increased exposure for obese subjects receiving 10 mg/kg belimumab did not lead to an overall increase in AE rates or serious AEs compared to obese subjects receiving placebo. However, higher rates of nausea, vomiting and diarrhoea were observed in obese patients. None of these gastrointestinal events in obese patients were serious.
No dose adjustment is recommended for underweight or obese subjects.
5.3 Preclinical safety data
Nonclinical data reveal no special hazard for humans based on studies of repeated dose toxicity and toxicity to reproduction.
Intravenous and subcutaneous administration to monkeys resulted in the expected reduction in the number of peripheral and lymphoid tissue B cell counts with no associated toxicological findings.
Reproductive studies have been performed in pregnant cynomolgus monkeys receiving belimumab 150 mg/kg by intravenous infusion (approximately 9 times the anticipated maximum human clinical exposure) every 2 weeks for up to 21 weeks, and Benlysta treatment was not associated with direct or indirect harmful effects with respect to maternal toxicity, developmental toxicity, or teratogenicity. Treatment-related findings were limited to the expected reversible reduction of B cells in both dams and infants and reversible reduction of IgM in infant monkeys. B cell numbers recovered after the cessation of belimumab treatment by about 1 year post-partum in adult monkeys and by 3 months of life in infant monkeys; IgM levels in infants exposed to belimumab in utero recovered by 6 months of age.
Effects on male and female fertility in monkeys were assessed in the 6-month repeat dose toxicology studies of belimumab at doses up to and including 50 mg/kg. No treatment-related changes were noted in the male and female reproductive organs of sexually mature animals. An informal assessment of menstrual cycling in females demonstrated no belimumab-related changes.
As belimumab is a monoclonal antibody no genotoxicity studies have been conducted. No carcinogenicity studies or fertility studies (male or female) have been performed.
6. Pharmaceutical particulars
6.1 List of excipients
Citric acid monohydrate (E330)
Sodium citrate (E331)
Sucrose
Polysorbate 80
6.2 Incompatibilities
Belimumab is not compatible with 5% glucose.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
6.3 Shelf life
Unopened vials
5 years.
Reconstituted solution
After reconstitution with water for injections, the reconstituted solution, if not used immediately, should be protected from direct sunlight, and stored refrigerated at 2°C - 8°C.
Reconstituted and diluted solution for infusion
Solution of Benlysta diluted in sodium chloride 9 mg/ml (0.9%) solution for injection may be stored at 2°C-8°C or room temperature (15°C - 25°C).
The total time from reconstitution of Benlysta to completion of infusion should not exceed 8 hours.
6.4 Special precautions for storage
Unopened vials
Store in a refrigerator (2°C - 8°C).
Do not freeze.
Store in the original carton in order to protect from light.
For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.
6.5 Nature and contents of container
120 mg vial:
Type 1 glass vials (5 ml), sealed with a latex-free, siliconised chlorobutyl rubber stopper and a flip-off aluminum seal.
400 mg vial:
Type 1 glass vials (20 ml), sealed with a latex-free, siliconised chlorobutyl rubber stopper and a flip-off aluminum seal.
Pack size: 1 vial
6.6 Special precautions for disposal and other handling
Preparation of the solution for infusion
Reconstitution
Reconstitution and dilution must be carried out under aseptic conditions.
Allow 10-15 minutes for the vial to warm to room temperature (15°C - 25°C).
The 120 mg single-use vial of belimumab is reconstituted with 1.5 ml of water for injections to yield a final concentration of 80 mg/ml belimumab.
The 400 mg single-use vial of belimumab is reconstituted with 4.8 ml of water for injections to yield a final concentration of 80 mg/ml belimumab.
The stream of water for injections 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 (15°C - 25°C) 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 water has been added, but it may take up to 30 minutes.
Protect the reconstituted solution from sunlight.
If a mechanical reconstitution device is used to reconstitute Benlysta it should not exceed 500 rpm and the vial should be 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.
After reconstitution, a volume of 1.5 ml (corresponding to 120 mg belimumab) can be withdrawn from each vial.
After reconstitution, a volume of 5 ml (corresponding to 400 mg belimumab) can be withdrawn from each vial.
Dilution
The reconstituted medicinal product is diluted to 250 ml with sodium chloride 9 mg/ml (0.9%) solution for injection.
5% glucose intravenous solutions are incompatible with Benlysta and must not be used.
From a 250 ml infusion bag or bottle of sodium chloride 9 mg/ml (0.9%) solution for injection, withdraw and discard a volume equal to the volume of the reconstituted Benlysta solution required for the patient's dose. Then add the required volume of the reconstituted Benlysta solution 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.
Inspect the Benlysta solution visually for particulate matter and discoloration prior to administration. Discard the solution if any particulate matter or discoloration is observed.
The total time from reconstitution of Benlysta to completion of infusion should not exceed 8 hours.
Method of administration
Benlysta is infused over a 1 hour period.
Benlysta should not be infused concomitantly in the same intravenous line with other agents. No physical or biochemical compatibility studies have been conducted to evaluate the co-administration of Benlysta with other agents.
No incompatibilities between Benlysta and polyvinylchloride or polyolefin bags have been observed.
Disposal
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. Marketing authorisation holder
Glaxo Group Limited
980 Great West Road
Brentford
Middlesex TW8 9GS
United Kingdom
8. Marketing authorisation number(s)
EU/1/11/700/001 - Benlysta 120 mg - Powder for concentrate for solution for infusion
EU/1/11/700/002 - Benlysta 400 mg - Powder for concentrate for solution for infusion
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 13 July 2011
10. Date of revision of the text
25 April 2014
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu