Leaflet BENLYSTA 120mg powder for concentrate infusion solution

Benlysta 200 mg solution for injection in pre-filled syringe.

Each 1 mL pre-filled syringe contains 200 mg of belimumab.

Belimumab is a human, IgG1λ monoclonal antibody, produced in a mammalian cell line (NS0) byrecombinant DNA technology.

Each pre-filled syringe contains 0.1 mg polysorbate 80.

For the full list of excipients, see section 6.1.

Solution for injection in pre-filled syringe (injection)

A clear to opalescent, colourless to pale yellow solution, with a pH of 6 and an osmolality of270 - 320 mOsm/kg.

Benlysta is indicated as add-on therapy in adult patients with active, autoantibody-positive systemic lupuserythematosus (SLE) with a high degree of disease activity (e.g., positive anti-dsDNA and low complement)despite standard therapy (see section 5.1).

Benlysta is indicated in combination with background immunosuppressive therapies for the treatment ofadult patients with active lupus nephritis (see sections 4.2 and 5.1).

Benlysta treatment should be initiated and supervised by a qualified physician experienced in the diagnosisand treatment of SLE. It is recommended that the first subcutaneous injection of Benlysta is given under thesupervision of a healthcare professional in a setting that is sufficiently qualified to manage hypersensitivityreactions, if necessary. The healthcare professional must provide proper training in subcutaneous techniqueand education about signs and symptoms of hypersensitivity reactions (see section 4.4). A patient may self-inject, or the patient caregiver may administer Benlysta after the healthcare professional determines that it isappropriate.

SLE

The recommended dose is 200 mg once weekly, administered subcutaneously. Dosing is not based on weight(see section 5.2). The patient’s condition should be evaluated continuously. Discontinuation of treatmentwith Benlysta is to be considered if there is no improvement in disease control after 6 months of treatment.

Lupus nephritis

In patients initiating therapy with Benlysta for active lupus nephritis, the recommended dosage regimen is a400 mg dose (two 200 mg injections) once weekly for 4 doses, then 200 mg once weekly thereafter. Inpatients continuing therapy with Benlysta for active lupus nephritis, the recommended dosage is 200 mgonce weekly. Benlysta is to be used in combination with corticosteroids and mycophenolate orcyclophosphamide for induction, or mycophenolate or azathioprine for maintenance. The patient’s conditionshould be evaluated continuously.

If a dose is missed, it is recommended to be administered as soon as possible. Thereafter, patients can resumedosing on their usual day of administration, or start a new schedule from the day that the missed dose wasadministered.

Changing the scheduled dosing day

If patients wish to change their scheduled dosing day, a new dose can be given on the newly preferred day ofthe week. Thereafter the patient can continue with the new schedule from that day, even if the dosing intervalmay be temporarily less than usual.

Transition from intravenous to subcutaneous administration

SLE

If a patient with SLE is being transitioned from Benlysta intravenous administration to subcutaneousadministration, the first subcutaneous injection must be administered 1 to 4 weeks after the last intravenousdose (see section 5.2).

Lupus nephritis

If a patient with lupus nephritis is being transitioned from Benlysta intravenous administration tosubcutaneous administration, it is recommended that the first dose of 200 mg subcutaneous injection beadministered 1 to 2 weeks after the last intravenous dose. This transition can occur any time after the patientcompletes the first 2 intravenous doses (see section 5.2).

Data on patients ≥ 65 years are limited (see section 5.1). Benlysta should be used with caution in the elderly.

Dose adjustment is not required (see section 5.2).

Belimumab has been studied in a limited number of SLE patients with renal impairment. On the basis of theavailable information, dose adjustment is not required in patients with mild, moderate or severe renalimpairment. Caution is however recommended in patients with severe renal impairment due to the lack ofdata (see section 5.2).

No specific studies with Benlysta have been conducted in patients with hepatic impairment. Patients withhepatic impairment are unlikely to require dose adjustment (see section 5.2).

SLE

In patients 5 years to less than 18 years of age, subcutaneous administration of Benlysta with the pre-filledsyringe has not been evaluated and subcutaneous administration of Benlysta with the pre-filled pen isrecommended. Currently available data are described in sections 4.8, 5.1 and 5.2, but no recommendation ona posology can be made with Benlysta in a pre-filled syringe.

The safety and efficacy of Benlysta subcutaneous administration in children under 5 years of age or less than15 kg have not been established. No data are available.

Lupus nephritis

The safety and efficacy of Benlysta subcutaneous administration in children and adolescents under 18 yearsof age have not been established. No data are available.

The pre-filled syringe must be used for subcutaneous injection only. The recommended injection sites are theabdomen or thigh. When injecting in the same region, patients must be advised to use a different injectionsite for each injection; injections must not be given into areas where the skin is tender, bruised, red, or hard.

When a 400 mg dose is administered at the same site, it is recommended that the 2 individual 200 mginjections are administered at least 5 cm (approximately 2 inches) apart.

Comprehensive instructions for subcutaneous administration of Benlysta in a pre-filled syringe are providedat the end of the package leaflet (see Step-by-step instructions).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

In order to improve traceability of biological medicinal products, the tradename and the batch number of theadministered product should be clearly recorded.

Benlysta has not been studied in the following patient groups and is not recommended in:

* severe active central nervous system lupus

* 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 renaltransplant.

Concomitant use with B cell targeted therapy

Available data do not support the co-administration of rituximab with Benlysta in patients with SLE (seesection 5.1). Caution needs to be exercised if Benlysta is co-administered with other B cell targeted therapy.

Administration of subcutaneous or intravenous Benlysta may result in hypersensitivity reactions which canbe severe, and fatal. In the event of a severe reaction, Benlysta administration must be interrupted andappropriate medical therapy administered (see section 4.2). The risk of hypersensitivity reactions is greatestwith the first two doses; however, the risk must be considered for every administration. Patients with ahistory of multiple drug allergies or significant hypersensitivity may be at increased risk. Recurrence ofclinically significant reactions after initial appropriate treatment of symptoms has also been observed (seesections 4.2 and 4.8).

Patients must be advised that hypersensitivity reactions are possible, on the day of, or several days afteradministration, and be informed of potential signs and symptoms and the possibility of recurrence. Patientsmust be instructed to seek immediate medical attention if they experience any of these symptoms. Thepackage leaflet must be available to the patient. Delayed-type, non-acute hypersensitivity reactions have alsobeen observed and included symptoms such as rash, nausea, fatigue, myalgia, headache, and facial oedema.

In intravenous clinical studies, serious infusion and hypersensitivity reactions included anaphylactic reaction,bradycardia, hypotension, angioedema, and dyspnoea. Please refer to the Summary of Product

Characteristics for Benlysta powder for concentrate for solution for infusion (section 4.4).

The mechanism of action of belimumab could increase the risk for the development of infections in adultsand children with lupus, including opportunistic infections, and younger children may be at increased risk. Incontrolled clinical studies, the incidence of serious infections was similar across the Benlysta and placebogroups; however, fatal infections (e.g. pneumonia and sepsis) occurred more frequently in patients receiving

Benlysta compared with placebo (see section 4.8). Pneumococcal vaccination should be considered beforeinitiating Benlysta treatment. Benlysta must not be initiated in patients with active serious infections(including serious chronic infections). Physicians need to exercise caution and carefully assess if the benefitsare expected to outweigh the risks when considering the use of Benlysta in patients with a history ofrecurrent infection. Physicians need to advise patients to contact their health care provider if they developsymptoms of an infection. Patients who develop an infection while undergoing treatment with Benlysta mustbe monitored closely and careful consideration given to interrupting immunosuppressant therapy including

Benlysta until the infection is resolved. The risk of using Benlysta in patients with active or latenttuberculosis is unknown.

Depression and suicidality

In controlled clinical intravenous and subcutaneous studies, psychiatric disorders (depression, suicidalideation and behaviour including suicides) have been reported more frequently in patients receiving Benlysta(see section 4.8). Physicians should assess the risk of depression and suicide considering the patient’smedical history and current psychiatric status before treatment with Benlysta and continue to monitorpatients during treatment. Physicians must advise patients (and caregivers where appropriate) to contact theirhealth care provider about new or worsening psychiatric symptoms. In patients who experience suchsymptoms, treatment discontinuation is to be considered.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which can be life-threatening orfatal, have been reported in association with Benlysta treatment. Patients should be advised of the signs andsymptoms of SJS and TEN and monitored closely for skin reactions. If signs and symptoms suggestive ofthese reactions appear, Benlysta should be withdrawn immediately, and an alternative treatment should beconsidered. If the patient has developed SJS or TEN with the use of Benlysta, treatment with Benlysta mustnot be restarted in this patient at any time.

Progressive multifocal leukoencephalopathy (PML) has been reported with Benlysta treatment for SLE.

Physicians must 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 newor worsening symptoms or signs, and if such symptoms/signs occur, referral to a neurologist and appropriatediagnostic measures for PML must be considered as clinically indicated. If PML is suspected,immunosuppressant therapy, including Benlysta, must be suspended until PML has been excluded. If PML isconfirmed, immunosuppressant therapy, including Benlysta, must be discontinued.

Live vaccines should not be given for 30 days before, or concurrently with Benlysta, as clinical safety hasnot been established. No data are available on the secondary transmission of infection from persons receivinglive vaccines to patients receiving Benlysta.

Because of its mechanism of action, belimumab may interfere with the response to immunisations. However,in a small study evaluating the response to a 23-valent pneumococcal vaccine, overall immune responses tothe different serotypes were similar in SLE patients receiving Benlysta compared with those receivingstandard immunosuppressive treatment at the time of vaccination. There are insufficient data to drawconclusions regarding response to other vaccines.

Limited data suggest that Benlysta does not significantly affect the ability to maintain a protective immuneresponse to immunisations received prior to administration of Benlysta. In a substudy, a small group ofpatients who had previously received either tetanus, pneumococcal or influenza vaccinations were found tomaintain protective titres after treatment with Benlysta.

Immunomodulatory medicinal products, including Benlysta, may increase the risk of malignancy. Caution isadvised when considering Benlysta therapy for patients with a history of malignancy or when consideringcontinuing treatment in patients who develop malignancy. Patients with malignant neoplasm within the last5 years have not been studied, with the exception of those with basal or squamous cell cancers of the skin, orcancer of the uterine cervix, that has been fully excised or adequately treated.

Polysorbate 80 content

This medicinal product contains polysorbate 80 (see section 2), which may cause allergic reactions.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium-free’.

No in vivo interaction studies have been performed. The formation of some CYP450 enzymes is suppressedby increased levels of certain cytokines during chronic inflammation. It is not known if belimumab could bean indirect modulator of such cytokines. A risk for indirect reduction of CYP activity by belimumab cannotbe excluded. On initiation or discontinuation of belimumab, therapeutic monitoring is to be considered forpatients being treated with CYP substrates with a narrow therapeutic index, where the dose is individuallyadjusted (e.g. warfarin).

Women of childbearing potential must use effective contraception during Benlysta treatment and for at least4 months after the last treatment.

There are a limited amount of data from the use of Benlysta in pregnant women. Besides an expectedpharmacological effect i.e. reduction of B cells, animal studies in monkeys do not indicate direct or indirectharmful effects with respect to reproductive toxicity (see section 5.3). Benlysta should not be used duringpregnancy unless the potential benefit justifies the potential risk to the foetus.

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 body weightevery 2 weeks.

Because maternal antibodies (IgG) are excreted in breast milk, it is recommended that a decision is made onwhether to discontinue breast-feeding or to discontinue Benlysta therapy, taking into account the benefit ofbreast-feeding for the child and the benefit of therapy for the woman.

There are no data on the effects of belimumab on human fertility. Effects on male and female fertility havenot been formally evaluated in animal studies (see section 5.3).

No studies on the effects on the ability to drive and use machines have been performed. No detrimentaleffects on such activities are predicted from the pharmacology of belimumab. It is recommended that theclinical status of the subject and the adverse reaction profile of Benlysta be borne in mind when consideringthe patient's ability to perform tasks that require judgement, motor or cognitive skills.

The safety of belimumab in patients with SLE has been evaluated in three pre-registration placebo-controlledintravenous studies and one subsequent regional placebo-controlled intravenous study, one placebo-controlled subcutaneous study, and two post-marketing placebo-controlled intravenous studies; the safety inpatients with active lupus nephritis has been evaluated in one placebo-controlled intravenous study.

The data presented in the table below reflect exposure in 674 patients with SLE from the three pre-registration clinical studies and 470 patients in the subsequent placebo-controlled study administered

Benlysta intravenously (10 mg/kg body weight over a 1-hour period on Days 0, 14, 28, and then every28 days for up to 52 weeks), and 556 patients with SLE exposed to Benlysta subcutaneously (200 mg onceweekly up to 52 weeks). The safety data presented include data beyond Week 52 in some patients with SLE.

The data reflect additional exposure in 224 patients with active lupus nephritis who received Benlystaintravenously (10 mg/kg body weight for up to 104 weeks). Data from post-marketing reports are alsoincluded.

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-inflammatorymedicinal products.

Adverse reactions were reported in 84 % of Benlysta-treated patients and 87 % of placebo-treated patients.

The most frequently reported adverse reaction (≥ 5 % of patients with SLE treated with Benlysta plusstandard of care and at a rate ≥ 1 % greater than placebo) was nasopharyngitis. The proportion of patientswho discontinued treatment due to adverse reactions was 7 % for Benlysta-treated patients and 8 % forplacebo-treated patients.

The most frequently reported adverse reactions (> 5 % of patients with active lupus nephritis treated with

Benlysta plus standard of care) were upper respiratory tract infection, urinary tract infection, and herpeszoster. The proportion of patients who discontinued treatment due to adverse reactions was 12.9 % for

Benlysta-treated patients and 12.9 % for placebo-treated patients.

Severe cutaneous adverse reactions: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)have been reported in association with Benlysta treatment (see section 4.4).

Adverse reactions are listed below by MedDRA system organ class and by frequency. The frequencycategories used are:

Very common  1/10

Common  1/100 to < 1/10

Uncommon  1/1000 to < 1/100

Rare  1/10 000 to < 1/1000

Not known cannot be estimated from the available data.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Thefrequency given is the highest seen with either formulation.

System organ class Frequency Adverse reactions

Infections and infestations1 Very common Bacterial infections, e.g. bronchitis,urinary tract infection

Common Gastroenteritis viral, pharyngitis,nasopharyngitis, viral upperrespiratory tract infection

Blood and lymphatic system Common Leucopeniadisorders

Immune system disorders Common Hypersensitivity reactions2

Uncommon Anaphylactic reaction

Rare Delayed-type, non-acutehypersensitivity reactions

Psychiatric disorders Common Depression

Uncommon Suicidal behaviour, suicidal ideation

Nervous system disorders Common Migraine

Gastrointestinal disorders Common Diarrhoea, nausea

Skin and subcutaneous tissue Common Injection site reactions3, urticaria,disorders rash

Uncommon Angioedema

Not known Stevens-Johnson syndrome, toxicepidermal necrolysis

Musculoskeletal and Common Pain in extremityconnective tissue disorders

General disorders and Common Infusion or injection-related systemicadministration site conditions reactions2, pyrexia1 See ‘Description of selected adverse reactions’ and section 4.4 ‘Infections’ for further information.2 ‘Hypersensitivity reactions’ covers a group of terms, including anaphylaxis, and can manifest as a range ofsymptoms including hypotension, angioedema, urticaria or other rash, pruritus, and dyspnoea. ‘Infusion orinjection-related systemic reactions’ covers a group of terms and can manifest as a range of symptomsincluding bradycardia, myalgia, headache, rash, urticaria, pyrexia, hypotension, hypertension, dizziness, andarthralgia. Due to overlap in signs and symptoms, it is not possible to distinguish between hypersensitivityreactions and infusion or injection-related systemic reactions in all cases.3 Applies to subcutaneous formulation only.

Data presented below are pooled from the three pre-registration intravenous clinical studies (10 mg/kg bodyweight intravenous dose only) and the subcutaneous clinical study. ‘Infections’ and ‘Psychiatric disorders’also include data from a post-marketing study.

Infusion or injection-related systemic reactions and hypersensitivity: Infusion or injection-related systemicreactions and hypersensitivity were generally observed on the day of administration, but acutehypersensitivity reactions may also occur several days after dosing. Patients with a history of multiple drugallergies or significant hypersensitivity reactions may be at increased risk.

The incidence of infusion reactions and hypersensitivity reactions after intravenous administration occurringwithin 3 days of an infusion was 12 % in the group receiving Benlysta and 10 % in the group receivingplacebo, with 1.2 % and 0.3 %, respectively, requiring permanent treatment discontinuation.

The incidence of post-injection systemic reactions and hypersensitivity reactions occurring within 3 days ofsubcutaneous administration was 7 % in the group receiving Benlysta and 9 % in the group receivingplacebo. Clinically significant hypersensitivity reactions associated with Benlysta administeredsubcutaneously and requiring permanent treatment discontinuation were reported in 0.2 % of patientsreceiving Benlysta and in no patients receiving placebo.

Infections: The overall incidence of infections in intravenous and subcutaneous pre-registration SLE studieswas 63 % in both groups receiving Benlysta or placebo. Infections occurring in at least 3 % of patientsreceiving Benlysta and at least 1 % more frequently than patients receiving placebo were viral upperrespiratory tract infection, bronchitis, and urinary tract infection bacterial. Serious infections occurred in 5 %of patients in both groups receiving Benlysta or placebo; serious opportunistic infections accounted for0.4 % and 0 % of these, respectively. Infections leading to discontinuation of treatment occurred in 0.7 % ofpatients receiving Benlysta and 1.5 % of patients receiving placebo. Some infections were severe or fatal.

For information on infections observed in paediatric patients with SLE see Paediatric population sectionbelow.

In the lupus nephritis study, patients were receiving a background of standard therapy (see section 5.1) andthe overall incidence of infections was 82 % in patients receiving Benlysta compared with 76 % in patientsreceiving placebo. Serious infections occurred in 13.8 % of patients receiving Benlysta and in 17.0 % ofpatients receiving placebo. Fatal infections occurred in 0.9 % (2/224) of patients receiving Benlysta and in0.9 % (2/224) of patients receiving placebo.

In a randomised, double-blind, 52-week, post-marketing safety SLE study (BEL115467) which assessedmortality and specific adverse events in adults, serious infections occurred in 3.7 % of patients receiving

Benlysta (10 mg/kg body weight intravenously) vs. 4.1 % of patients receiving placebo. However, fatalinfections (e.g. pneumonia and sepsis) occurred in 0.45 % (9/2002) of Benlysta-treated patients vs. 0.15 %(3/2001) of patients receiving placebo, while the incidence of all-cause mortality was 0.50 % (10/2002) vs.

0.40 % (8/2001), respectively. Most fatal infections were observed during the first 20 weeks of treatmentwith Benlysta.

Psychiatric disorders: In the pre-registration intravenous SLE clinical studies, serious psychiatric eventswere reported in 1.2 % (8/674) of patients receiving Benlysta 10 mg/kg body weight and 0.4 % (3/675) ofpatients receiving placebo. Serious depression was reported in 0.6 % (4/674) of patients receiving Benlysta10 mg/kg body weight and 0.3 % (2/675) of patients receiving placebo. There were two suicides in Benlysta-treated patients (including one receiving Benlysta 1 mg/kg body weight).

In a post-marketing SLE study, serious psychiatric events were reported in 1.0 % (20/2002) of patientsreceiving Benlysta and 0.3 % (6/2001) of patients receiving placebo. Serious depression was reported in0.3 % (7/2002) of patients receiving Benlysta and < 0.1 % (1/2001) of patients receiving placebo. Theoverall incidence of serious suicidal ideation or behaviour or self-injury without suicidal intent was 0.7 %(15/2002) in patients receiving Benlysta and 0.2 % (5/2001) in the placebo group. No suicide was reported ineither group.

The intravenous SLE studies above did not exclude patients with a history of psychiatric disorders.

In the subcutaneous SLE clinical study, which excluded patients with a history of psychiatric disorders,serious psychiatric events were reported in 0.2 % (1/556) of patients receiving Benlysta and in no patientsreceiving placebo. There were no serious depression-related events or suicides reported in either group.

Leucopenia: The incidence of leucopenia reported in patients with SLE as an adverse event was 3 % in thegroup receiving Benlysta and 2 % in the group receiving placebo.

Injection site reactions: In the subcutaneous SLE study, the frequency of injection site reactions was 6.1 %(34/556) and 2.5 % (7/280) for patients receiving Benlysta and placebo, respectively. These injection sitereactions (most commonly pain, erythema, hematoma, pruritus and induration) were mild to moderate inseverity. The majority did not necessitate drug discontinuation.

The adverse reaction profile in paediatric patients is based on one subcutaneous study and one intravenousstudy.

In a 52-week open-label study in which 25 paediatric patients (10 to 17 years of age) with SLE receivedsubcutaneous Benlysta at a comparable exposure to adults (200 mg at a set dosing interval based on bodyweight, on a background of concomitant treatments), the safety profile in paediatric patients receiving

Benlysta subcutaneously was consistent with the known safety profile for belimumab.

In a 52-week placebo-controlled study in which 53 patients (6 to 17 years of age) with SLE received

Benlysta (10 mg/kg body weight intravenously on Days 0, 14, 28, and then every 28 days, on a backgroundof concomitant treatments), no new safety signals were observed in the paediatric population 12 years of ageand above (n = 43). Safety data in children younger than 12 years of age (n = 10) are limited.

Infections5- to 11-year-old group: infections were reported in 8/10 patients receiving Benlysta intravenously and3/3 patients receiving placebo, and serious infections were reported in 1/10 patients receiving Benlystaintravenously and 2/3 patients receiving placebo (see section 4.4).

12- to 17-year-old group: infections were reported in 22/43 patients receiving Benlysta intravenously and25/37 patients receiving placebo, and serious infections were reported in 3/43 patients receiving Benlystaintravenously and 3/37 patients receiving placebo. In the open-label extension phase there was one fatalinfection in a patient receiving Benlysta intravenously.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are askedto report any suspected adverse reactions via the national reporting system listed in Appendix V.

There is limited clinical experience with overdose of Benlysta. Adverse reactions reported in associationwith cases of overdose have been consistent with those expected for belimumab.

Two doses up to 20 mg/kg body weight administered 21 days apart by intravenous infusion have been givento humans with no increase in incidence or severity of adverse reactions compared with doses of 1, 4, or10 mg/kg body weight.

In the case of inadvertent overdose, patients should be carefully observed and supportive care administered,as appropriate.

Pharmacotherapeutic group: Immunosuppressants, monoclonal antibodies, ATC code: L04AG04

Belimumab is a human IgG1 monoclonal antibody specific for soluble human B Lymphocyte Stimulatorprotein (BLyS, also referred to as BAFF and TNFSF13B). Belimumab blocks the binding of soluble BLyS, a

B cell survival factor, to its receptors on B cells. Belimumab does not bind B cells directly, but by binding

BLyS, belimumab inhibits the survival of B cells, including autoreactive B cells, and reduces thedifferentiation of B cells into immunoglobulin-producing plasma cells.

BLyS levels are elevated in patients with SLE and other autoimmune diseases. There is an associationbetween plasma BLyS levels and SLE disease activity. The relative contribution of BLyS levels to thepathophysiology of SLE is not fully understood.

Median IgG levels at Week 52 were reduced by 11 % in patients with SLE receiving Benlysta comparedwith an increase of 0.7 % in patients receiving placebo.

In patients with anti-dsDNA antibodies at baseline, median anti-dsDNA antibodies levels at Week 52 werereduced by 56 % in patients receiving Benlysta compared with 41 % in patients receiving placebo. Inpatients with anti-dsDNA antibodies at baseline, by Week 52, 18 % of patients treated with Benlysta hadconverted to anti-dsDNA negative compared with 15 % of the patients receiving placebo.

In patients with SLE with low complement levels, normalization of C3 and C4 was observed by Week 52 in42 % and 53 % of patients receiving Benlysta and in 21 % and 20 % of patients receiving placebo,respectively.

Benlysta significantly reduced circulating overall, transitional, naïve, and SLE B cells, as well as plasmacells at Week 52. Reductions in naïve and transitional B cells, as well as the SLE B cell subset wereobserved as early as Week 8. Memory cells increased initially and slowly declined toward baseline levels by

Week 52.

The B cell and IgG response to long term treatment with intravenous Benlysta was assessed in anuncontrolled SLE extension study. After 7 and a half years of treatment (including the 72-week parentstudy), a substantial and sustained decrease in various B cell subsets was observed leading to 87 % medianreduction in naïve B cells, 67 % in memory B cells, 99 % in activated B cells, and 92 % median reduction inplasma cells after more than 7 years of treatment. After about 7 years, a 28 % median reduction in IgG levelswas observed, with 1.6 % of subjects experiencing a decrease in IgG levels to below 400 mg/dL. Over thecourse of the study, the reported incidence of AEs generally remained stable or declined.

In patients with active lupus nephritis, following treatment with Benlysta (10 mg/kg body weightintravenously) or placebo, there was an increase in serum IgG levels which was associated with decreasedproteinuria. Relative to placebo, smaller increases in serum IgG levels were observed in the Benlysta groupas expected with the known mechanism of belimumab. At Week 104, the median percent increase frombaseline in IgG was 17 % for Benlysta and 37 % for placebo. Reductions in autoantibodies, increases incomplement, and reductions in circulating total B cells and B-cell subsets observed were consistent with the

SLE studies.

In one intravenous study in paediatric patients with SLE (6 to 17 years of age) and one subcutaneous study inpaediatric patients with SLE (10 to 17 years of age), the pharmacodynamic response was consistent with theadult data (see section 4.2).

In the subcutaneous study where serum samples from more than 550 adult patients with SLE were tested, noanti-belimumab antibodies were detected during or after treatment with belimumab 200 mg subcutaneously.

In the lupus nephritis study where 224 adult patients received Benlysta 10 mg/kg body weight intravenously,no anti-belimumab antibodies were detected.

In one intravenous study in 6- to 17-year-old paediatric patients (n = 53) with SLE and one subcutaneousstudy in 10- to 17-year-old paediatric patients (n = 25) with SLE, none of the patients developedanti-belimumab antibodies (see section 4.2).

SLE

The efficacy of Benlysta administered subcutaneously was evaluated in a randomised, double-blind,placebo-controlled 52-week Phase III study (HGS1006-C1115; BEL112341) in 836 adult patients with aclinical diagnosis of SLE according to the American College of Rheumatology classification criteria.

Eligible patients had active SLE disease, defined as a SELENA-SLEDAI score ≥ 8 and positive anti-nuclearantibody (ANA or anti-dsDNA) 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 (standard of care) consisting of any of thefollowing (alone or in combination): corticosteroids, anti-malarials, NSAIDs or other immunosuppressives.

Patients were excluded from the study if they had severe active central nervous system lupus or severe activelupus nephritis.

This study was conducted in the US, South America, Europe and Asia. Patient median age was 37 years(range: 18 to 77 years), and the majority (94 %) were female. Background medicinal products includedcorticosteroids (86 %; > 7.5 mg/day prednisone equivalent 60 %), immunosuppressives (46 %), andanti-malarials (69 %). Patients were randomised in a 2:1 ratio to receive belimumab 200 mg or placebosubcutaneously once weekly for 52 weeks.

At baseline 62.2 % of patients had high disease activity (SELENA SLEDAI score ≥ 10), 88 % of patientshad mucocutaneous, 78 % had musculoskeletal, 8 % had haematological, 12 % had renal, and 8 % hadvascular organ involvement.

The primary efficacy endpoint was a composite endpoint (SLE Responder Index) that defined response asmeeting 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 organsystem, or in the patient’s overall condition.

Table 1. Response rate at Week 52

Response1 Placebo2 Benlysta2200 mg weekly(n = 279) (n = 554)

SLE responder index 48.4 % 61.4 %(p = 0.0006)

Observed difference vs. placebo 12.98 %

Odds ratio (95 % CI) vs. placebo 1.68(1.25, 2.25)

Components of SLE responder index

Percent of patients with reduction in 49.1 % 62.3 %

SELENA-SLEDAI  4 (p = 0.0005)

Percent of patients with no worsening by BILAG 74.2 % 80.9 %index (p = 0.0305)

Percent of patients with no worsening by PGA 72.8 % 81.2 %(p = 0.0061)1 Analyses excluded any subject missing a baseline assessment for any of the components (1 for placebo;2 for Benlysta).2 All patients received standard therapy.

The differences between the treatment groups were apparent by Week 16 and sustained through Week 52(Figure 1).

Figure 1. Proportion of SRI responders by visit

Benlysta + Standard therapy (n = 554)

Placebo + Standard therapy (n = 279)

* P < 0.05

Time (weeks)

Flares in SLE were defined by the modified SELENA SLEDAI SLE Flare Index. The risk of first flare wasreduced by 22 % during the 52 weeks of observation in the group receiving Benlysta compared with thegroup receiving placebo (hazard ratio = 0.78; p = 0.0061). The median time to the first flare among patientshaving a flare was delayed in patients receiving Benlysta compared with placebo (190 days vs. 141 days).

Severe flares were observed in 10.6 % of patients in the group receiving Benlysta compared with 18.2 % ofpatients in the group receiving placebo over the 52 weeks of observation (observed treatmentdifference = -7.6 %). The risk of severe flares was reduced by 49 % during the 52 weeks of observation inthe group receiving Benlysta compared with the group receiving placebo (hazard ratio = 0.51; p = 0.0004).

The median time to the first severe flare among patients having a severe flare was delayed in patientsreceiving Benlysta compared with placebo (171 days vs. 118 days).

Responders (%)

The percentage of patients receiving greater than 7.5 mg/day prednisone (or equivalent) at baseline whoseaverage corticosteroid dose was reduced by at least 25 % from baseline to a dose equivalent to prednisone≤ 7.5 mg/day during Weeks 40 through 52, was 18.2 % in the group receiving Benlysta and 11.9 % in thegroup receiving placebo (p = 0.0732).

Benlysta demonstrated improvement in fatigue compared with placebo measured by the FACIT-Fatigue

Scale. The adjusted mean change of score at Week 52 from baseline is significantly greater with Benlystacompared to placebo (4.4 vs. 2.7, p = 0.0130).

Subgroup analysis of the primary endpoint demonstrated that the greatest benefit was observed in patientswith higher disease activity at baseline including patients with SELENA SLEDAI scores ≥ 10 or patientsrequiring steroids to control their disease or patients with low complement levels.

An additional, previously identified serologically active group, those patients with low complement andpositive anti-dsDNA at baseline, also demonstrated a greater relative response, see Table 2 for results of thisexample of a higher disease activity group.

Table 2. Patients with low complement and positive anti-dsDNA at baseline

Anti-dsDNA positive AND low complement

Subgroup Placebo Benlysta200 mg weekly(n = 108) (n = 246)

SRI response rate at Week 521 (%) 47.2 64.6 (p = 0.0014)

Observed treatment difference vs. placebo (%) 17.41

Severe flares over 52 weeks: (n = 108) (n = 248)

Patients experiencing a severe flare (%) 31.5 14.1

Observed treatment difference vs. placebo (%) 17.4

Time to severe flare [Hazard ratio (95 % CI)] 0.38 (0.24, 0.61)(p < 0.0001)(n = 70) (n = 164)

Prednisone reduction by ≥ 25 % from baseline to 11.4 20.7 (p = 0.0844)≤ 7.5 mg/day during weeks 24 through 522 (%)

Observed treatment difference vs. placebo (%) 9.3(n = 108) (n = 248)

FACIT-fatigue score improvement from baseline at

Week 52 (mean): 2.4 4.6 (p = 0.0324)

Observed treatment difference vs. placebo (median 2.1difference)1 Analysis of SRI response rate at Week 52 excluded any subject missing a baseline assessment (2 for

Benlysta).2 Among patients with baseline prednisone dose > 7.5 mg/day.

The efficacy and safety of Benlysta in combination with a single cycle of rituximab have been studied in a

Phase III, randomised, double-blind, placebo-controlled 104-week study including 292 patients (BLISS-

BELIEVE). The primary endpoint was the proportion of subjects with a state of disease control defined as a

SLEDAI-2K score ≤ 2, achieved without immunosuppressants and with corticosteroids at a prednisoneequivalent dose of ≤ 5 mg/day at Week 52. This was achieved in 19.4 % (n = 28/144) of the patients treatedwith Benlysta in combination with rituximab and in 16.7 % (n = 12/72) of the patients treated with Benlystain combination with placebo (odds ratio 1.27; 95 % CI: 0.60, 2.71; p = 0.5342). A higher frequency ofadverse events (91.7 % vs. 87.5 %), serious adverse events (22.2 % vs. 13.9 %) and serious infections (9.0 %vs. 2.8 %) were observed in patients treated with Benlysta in combination with rituximab as compared to

Benlysta in combination with placebo.

Lupus nephritis

The efficacy and safety of Benlysta 200 mg administered subcutaneously to patients with active lupusnephritis is based on data from administration of Benlysta 10 mg/kg body weight intravenously andpharmacokinetic modelling and simulation (see section 5.2).

In the subcutaneous SLE study, described above, patients who had severe active lupus nephritis wereexcluded; however, 12 % of patients had renal organ domain involvement at baseline (based on SELENA

SLEDAI assessment). The following study in active lupus nephritis has been conducted.

Intravenous infusion

The efficacy and safety of Benlysta 10 mg/kg body weight administered intravenously over a 1-hour periodon Days 0, 14, 28, and then every 28 days, were evaluated in a 104-week randomised (1:1), double-blind,placebo-controlled, Phase III study (BEL114054) in 448 patients with active lupus nephritis. The patientshad a clinical diagnosis of SLE according to ACR classification criteria, biopsy proven lupus nephritis Class

III, IV, and/or V and had active renal disease at screening requiring standard therapy. Standard therapyincluded corticosteroids, 0 to 3 intravenous administrations of methylprednisolone (500 to1000 mg peradministration), followed by oral prednisone 0.5 to1 mg/kg/day with a total daily dose ≤60 mg/day andtapered to ≤ 10 mg/day by Week 24, with:

* mycophenolate mofetil 1 to 3 g/day orally or mycophenolate sodium 720 to 2160 mg/day orally forinduction and maintenance, or

* cyclophosphamide 500 mg intravenously every 2 weeks for 6 infusions for induction followed byazathioprine orally at a target dose of 2 mg/kg/day for maintenance.

This study was conducted in Asia, North America, South America, and Europe. Patient median age was31 years (range: 18 to 77 years); the majority (88 %) were female.

The primary efficacy endpoint was Primary Efficacy Renal Response (PERR) at Week 104 defined as aresponse at Week 100 confirmed by a repeat measurement at Week 104 of the following parameters: urinaryprotein:creatinine ratio (uPCR) ≤ 700 mg/g (79.5 mg/mmol) and estimated glomerular filtration rate (eGFR)≥ 60 mL/min/1.73 m2 or no decrease in eGFR of > 20 % from pre-flare value.

The major secondary endpoints included:

* Complete Renal Response (CRR) defined as a response at Week 100 confirmed by a repeatmeasurement at Week 104 of the following parameters: uPCR < 500 mg/g (56.8 mg/mmol) and eGFR≥ 90 mL/min/1.73 m2 or no decrease in eGFR of > 10 % from pre-flare value.

* PERR at Week 52.

* Time to renal-related event or death (renal-related event defined as first event of end-stage renaldisease, doubling of serum creatinine, renal worsening [defined as increased proteinuria, and/orimpaired renal function], or receipt of renal disease-related prohibited therapy).

For PERR and CRR endpoints, steroid treatment had to be reduced to ≤ 10 mg/day from Week 24 to beconsidered a responder. For these endpoints, patients who discontinued treatment early, received prohibitedmedication, or withdrew from the study early were considered non-responders.

The proportion of patients achieving PERR at Week 104 was significantly higher in patients receiving

Benlysta compared with placebo. The major secondary endpoints also showed significant improvement with

Benlysta compared with placebo (Table 3).

Table 3. Efficacy results in adult patients with lupus nephritis

Efficacy endpoint Placebo Benlysta Observed Odds/Hazard P-10 mg/kg difference ratio vs. valuevs. placebo placebo(n = 223) (n = 223) (95 % CI)

PERR at Week 1041 OR 1.55

Responders 32.3 % 43.0 % 10.8 % (1.04, 2.32) 0.0311

Components of PERR

Urine protein:creatinine OR 1.54ratio ≤ 700 mg/g 33.6 % 44.4 % 10.8 % (1.04, 2.29) 0.0320(79.5 mg/mmol)eGFR≥ 60 mL/min/1.73 m2or no decrease in eGFR OR 1.32from pre-flare value of 50.2 % 57.4 % 7.2 % (0.90, 1.94) 0.1599> 20 %

Not treatment failure³ OR 1.6574.4 % 83.0 % 8.5 % (1.03, 2.63) 0.0364

CRR at Week 1041 OR 1.74

Responders 19.7 % 30.0 % 10.3 % (1.11, 2.74) 0.0167

Components of CRR

Urine protein:creatinine OR 1.58ratio < 500 mg/g 28.7 % 39.5 % 10.8 % (1.05, 2.38) 0.0268(56.8 mg/mmol)eGFR≥ 90 mL/min/1.73 m2or no decrease in eGFR OR 1.33from pre-flare value of 39.9 % 46.6 % 6.7 % (0.90, 1.96) 0.1539> 10 %

Not treatment failure³ OR 1.6574.4 % 83.0 % 8.5 % (1.03, 2.63) 0.0364

PERR at Week 521 OR 1.59

Responders 35.4 % 46.6 % 11.2 % (1.06, 2.38) 0.0245

Time to renal-related eventor death1

Percentage of patients withevent2 28.3 % 15.7 % -

Time to event [Hazard ratio HR 0.51(95 % CI)] - (0.34, 0.77) 0.00141 PERR at Week 104 was the primary efficacy analysis; CRR at Week 104, PERR at Week 52 and time torenal-related event or death were included in the pre-specified testing hierarchy.2 When excluding deaths from the analysis (1 for Benlysta; 2 for placebo), the percentage of patients with arenal-related event was 15.2 % for Benlysta compared with 27.4 % for placebo (HR = 0.51; 95 % CI: 0.34,0.78).

³ Treatment failure: Patients who took protocol-prohibited medication.

A numerically greater percentage of patients receiving Benlysta achieved PERR beginning at Week 24compared with placebo, and this treatment difference was maintained through to Week 104. Beginning at

Week 12, a numerically greater percentage of patients receiving Benlysta achieved CRR compared withplacebo and the numerical difference was maintained through to Week 104 (Figure 2).

Figure 2. Response rates in adults with lupus nephritis by visit

Primary Efficacy Renal Response (PERR)

Benlysta + Standard therapy (n = 223)

Placebo + Standard therapy (n = 223)

Time (weeks)

Complete Renal Response (CRR)

Benlysta + Standard therapy (n = 223)

Placebo + Standard therapy (n = 223)

Time (weeks)

In descriptive subgroup analyses, key efficacy endpoints (PERR and CRR) were examined by inductionregimen (mycophenolate or cyclophosphamide) and biopsy class (Class III or IV, Class III + V or Class IV +

V, or Class V) (Figure 3).

Responders (%) +/- SE Responders (%) +/- SE

Figure 3. Odds ratio of PERR and CRR at Week 104 across subgroups

Subgroup Response rate

Benlysta (n) versus Placebo (n) Placebo Benlysta Odds ratio(%) (%) (95 % CI)

Favours Placebo Favours Benlysta

Induction regimen

Mycophenolate (164 vs. 164) 34 46 1.6 (1.0, 2.5)20 34 2.0 (1.2, 3.4)

Cyclophosphamide (59 vs. 59) 27 34 1.5 (0.7, 3.5)19 19 1.1 (0.4, 2.8)

Biopsy class

Class III or Class IV (126 vs. 132) 32 48 1.8 (1.1, 3.1)19 31 1.8 (1.0, 3.2)

Class III + V or Class IV + V (61 vs. 55)27 38 1.8 (0.8, 4.0)15 26 2.8 (1.0, 7.7)

Class V (36 vs. 36)42 36 0.6 (0.2, 1.9)31 33 0.8 (0.3, 2.6)0.1 0.2 0.5 1 2 4 8

Odds ratio

Primary Efficacy Renal Response (PERR)

Complete Renal Response (CRR)

Age and race

There were no observed differences in efficacy or safety in SLE patients ≥ 65 years who received Benlystaintravenously or subcutaneously compared to the overall population in placebo-controlled studies; however,the number of patients aged ≥ 65 years (62 patients for efficacy and 219 for safety) is not sufficient todetermine whether they respond differently to younger patients.

Black patients

There were too few black patients enrolled in the placebo-controlled studies with subcutaneous Benlysta todraw meaningful conclusions about the effects of race on clinical outcomes.

The safety and efficacy of Benlysta administered intravenously have been studied in black patients. Thecurrently available data are described in the Summary of Product Characteristics of Benlysta 120 mg and400 mg powder for concentrate for solution for infusion.

SLE

Benlysta 200 mg solution for injection in the pre-filled syringe has not been evaluated in paediatric patients(see section 4.2). For Benlysta 200 mg solution for injection in the pre-filled pen, the safety and efficacy of

Benlysta administered subcutaneously to paediatric patients 5 to < 18 years of age with active SLE issupported by a population pharmacokinetic model and simulation integrating data from an open-labelpharmacokinetic study of 25 paediatric patients with active SLE administered Benlysta subcutaneously(200908), and a study of paediatric patients with active SLE administered Benlysta intravenously (PLUTO)described below (see section 5.2).

Intravenous infusion

The safety and efficacy of Benlysta was evaluated in a randomised, double-blind, placebo-controlled,52-week study (PLUTO) in 93 paediatric patients with a clinical diagnosis of SLE according to the ACRclassification criteria. Patients had active SLE disease, defined as a SELENA-SLEDAI score ≥ 6 and positiveautoantibodies at screening as described in the adult trials. Patients were on a stable SLE treatment regimen(standard of care) and had similar inclusion criteria as the adult studies. Patients who had severe active lupusnephritis, severe active CNS lupus, primary immunodeficiency, IgA deficiency or acute or chronic infectionsrequiring management were excluded from the study. The study was conducted in the US, South America,

Europe, and Asia. Patient median age was 15 years (range 6 to 17 years). In the 5- to 11-year-old-group(n = 13) the SELENA-SLEDAI score ranged from 4 to 13, and in 12- to 17-year-old-group (n = 79) the

SELENA-SLEDAI score ranged from 4 to 20. The majority (94.6 %) of patients were female. The study wasnot powered for any statistical comparisons and all data are descriptive.

The primary efficacy endpoint was the SLE Responder Index (SRI) at Week 52 as described in the adultintravenous trials. There was a higher proportion of paediatric patients achieving an SRI response in patientsreceiving Benlysta compared with placebo. The response for the individual components of the endpoint wereconsistent with that of the SRI (Table 4).

Table 4. Paediatric response rate at Week 52

Placebo Benlysta10 mg/kg

Response1 (n = 40) (n = 53)

SLE Responder Index (%) 43.6 52.8(17/39) (28/53)

Odds ratio (95 % CI) vs. placebo 1.49 (0.64, 3.46)

Components of SLE Responder Index

Percent of patients with reduction in 43.6 54.7

SELENA-SLEDAI  4 (%) (17/39) (29/53)

Odds ratio (95 % CI) vs. placebo 1.62 (0.69, 3.78)

Percent of patients with no worsening by BILAG 61.5 73.6index (%) (24/39) (39/53)

Odds ratio (95 % CI) vs. placebo 1.96 (0.77, 4.97)

Percent of patients with no worsening by PGA (%) 66.7 75.5(26/39) (40/53)

Odds ratio (95 % CI) vs. placebo 1.70 (0.66, pct. 4.39)1 Analyses excluded any subject missing a baseline assessment for any of the components (1 for placebo).

Among patients experiencing a severe flare, the median study day of the first severe flare was Day 150 in the

Benlysta group and Day 113 in the placebo group. Severe flares were observed in 17.0 % of the Benlystagroup compared to 35.0 % of the placebo group over the 52 weeks of observation (observed treatmentdifference = 18.0 %; hazard ratio = 0.36, 95 % CI: 0.15, 0.86). This was consistent with the findings from theadult intravenous clinical trials.

Using the Paediatric Rheumatology International Trials Organisation/American College of Rheumatology(PRINTO/ACR) Juvenile SLE Response Evaluation Criteria, a higher proportion of paediatric patientsreceiving Benlysta demonstrated improvement compared with placebo (Table 5).

Table 5. PRINTO/ACR response rate at Week 52

Proportion of patients with at Proportion of patients with atleast 50 % improvement in any least 30 % improvement in 3 of2 of 5 components1 and no 5 components1 and no moremore than one of the remaining than one of the remainingworsening by more than 30 % worsening more than 30 %

Placebo Benlysta Placebo Benlysta10 mg/kg 10 mg/kgn = 40 n = 53 n = 40 n = 53

Response, n (%) 14/40 32/53 11/40 28/53(35.0) (60.4) (27.5) (52.8)

Observed difference vs. Placebo 25.38 25.33

Odds ratio (95 % CI) vs. Placebo 2.74 2.92(1.15, 6.54) (1.19, 7.17)1 The five PRINTO/ACR components were percent change at Week 52 in: Parent’s Global Assessment(Parent GA), PGA, SELENA SLEDAI score, 24-hour proteinuria, and, Paediatric Quality of Life

Inventory - Generic Core Scale (PedsQL GC) physical functioning domain score.

The subcutaneous pharmacokinetic parameters below are based on population parameter estimates from661 subjects, comprised of 554 SLE patients and 107 healthy subjects, who received Benlystasubcutaneously.

Benlysta in the pre-filled syringe is administered by subcutaneous injection.

Following subcutaneous administration, the bioavailability of belimumab was approximately 74 %.

Steady-state exposure was reached after approximately 11 weeks of subcutaneous administration. Themaximum serum concentration (Cmax) of belimumab at steady state was 108 µg/mL.

Belimumab was distributed to tissues with steady-state volume (Vss) of distribution of approximately5 litres.

Belimumab is a protein for which the expected metabolic pathway is degradation to small peptides andindividual amino acids by widely distributed proteolytic enzymes. Classical biotransformation studies havenot been conducted.

Following subcutaneous administration, belimumab had a terminal half-life of 18.3 days. The systemicclearance was 204 mL/day.

Lupus nephritis study

A population pharmacokinetic analysis was conducted in 224 adult patients with lupus nephritis whoreceived Benlysta 10 mg/kg body weight intravenously (Days 0, 14, 28, and then every 28 days up to104 weeks). In patients with lupus nephritis, due to renal disease activity, belimumab clearance was initiallyhigher than observed in SLE studies; however, after 24 weeks of treatment and throughout the remainder ofthe study, belimumab clearance and exposure were similar to that observed in adult patients with SLE whoreceived belimumab 10 mg/kg body weight intravenously.

Based on population pharmacokinetic modelling and simulation, the steady-state average concentrations ofsubcutaneous administration of belimumab 200 mg once weekly in adults with lupus nephritis are predictedto be similar to those observed in adults with lupus nephritis receiving belimumab 10 mg/kg body weightintravenously every 4 weeks.

Paediatric population: Benlysta 200 mg solution for injection in the pre-filled syringe has not been evaluatedin paediatric patients (see section 4.2). For Benlysta 200 mg solution for injection in the pre-filled pen, thepharmacokinetic parameters of belimumab administered subcutaneously are based on a populationpharmacokinetic analysis of 25 patients from a Phase II pharmacokinetic study in paediatric patients with

SLE receiving belimumab subcutaneously and the Phase II study in paediatric patients with SLE receivingbelimumab intravenously. Following subcutaneous administration of 200 mg of belimumab in paediatricpatients 5 to less than 18 years of age [weekly (patients weighing ≥ 50 kg), every 10 days (patients weighing30 to < 50 kg) or every 2 weeks (patients weighing 15 to < 30 kg)], the steady state average belimumabconcentration is estimated to be similar to that of adult SLE subjects following subcutaneous administrationof 200 mg belimumab weekly, and similar to that of paediatric SLE subjects following intravenousadministration of belimumab 10 mg/kg body weight on Days 0, 14 and 28, and at 4-week intervals thereafter.

Simulated steady-state geometric mean Cmax, Cavg, Cmin, and AUC (calculated over the dosing interval) areestimated to be 124 g/mL, 119 g/mL, 111 g/mL and 834 day*g/mL for paediatric patients weighing≥ 50 kg receiving belimumab once weekly, 114 g/mL, 105 g/mL, 91 g/mL and 1051 day*g/mL forpaediatric patients weighing 30 to < 50 kg receiving belimumab every 10 days, and 119 g/mL, 103 g/mL,79 g/mL and 1438 day*g/mL for paediatric patients weighing 15 to < 30 kg receiving belimumab every2 weeks.

Elderly: Benlysta has been studied in a limited number of elderly patients. Age did not affect belimumabexposure in the subcutaneous population pharmacokinetic analysis. However, given the small number ofsubjects ≥ 65, an effect of age cannot be ruled out conclusively.

Renal impairment: No specific studies have been conducted to examine the effects of renal impairment onthe pharmacokinetics of belimumab. During clinical development, Benlysta was studied in a limited numberof SLE patients with mild (creatinine clearance [CrCl]  60 and < 90 mL/min), moderate (CrCl  30 and< 60 mL/min), or severe (CrCl  15 and < 30 mL/min) renal impairment: 121 patients with mild renalimpairment and 30 patients with moderate renal impairment received Benlysta subcutaneously; 770 patientswith mild renal impairment, 261 patients with moderate renal impairment and 14 patients with severe renalimpairment received Benlysta intravenously.

No clinically significant reduction in systemic clearance as a result of renal impairment was observed.

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 impairmenton the pharmacokinetics of belimumab. IgG1 molecules such as belimumab are catabolised by widelydistributed proteolytic enzymes, which are not restricted to hepatic tissue and changes in hepatic function areunlikely to have any effect on the elimination of belimumab.

Body weight/Body mass index (BMI)

The effects of body weight and BMI on belimumab exposure after subcutaneous administration in adultswere not considered clinically meaningful. There was no significant impact on efficacy and safety based onweight. Therefore, no dose adjustment in adults is recommended.

The effects of body weight on belimumab exposure after subcutaneous administration in paediatric patientshave been determined using a population pharmacokinetic model. Paediatric patients with lower body weighthave lower belimumab clearance and volume of distribution resulting in increased exposure. To ensurebelimumab exposures remain within acceptable limits and are consistent across the paediatric weight range,patients with lower body weight are dosed belimumab less frequently (see section 4.2).

Transitioning from intravenous to subcutaneous administration

SLE

Patients with SLE transitioning from 10 mg/kg body weight intravenously every 4 weeks to a 200 mgsubcutaneous regimen using a 1 to 4 week switching interval had pre-dose belimumab serum concentrationsat their first subcutaneous dose close to their eventual subcutaneous steady-state trough concentration (seesection 4.2). Based on simulations with population pharmacokinetic parameters the steady-state averagebelimumab concentrations for 200 mg subcutaneous every week (in adult patients, and in paediatric patients5 to under 18 years of age and ≥ 50 kg), every 10 days (in paediatric patients 5 to under 18 years of age and30 to < 50 kg) or every 2 weeks (in paediatric patients 5 to under 18 years of age and 15 to < 30 kg), weresimilar to 10 mg/kg body weight intravenous every 4 weeks.

Lupus nephritis

One to 2 weeks after completing the first 2 intravenous doses, patients with lupus nephritis transitioning from10 mg/kg body weight intravenously to 200 mg subcutaneously weekly, are predicted to have averagebelimumab serum concentrations similar to patients dosed with 10 mg/kg body weight intravenously every4 weeks based on population pharmacokinetic simulations (see section 4.2).

Non-clinical data reveal no special hazard for humans based on studies of repeated dose toxicity and toxicityto reproduction.

Intravenous and subcutaneous administration to monkeys resulted in the expected reduction in the number ofperipheral and lymphoid tissue B cell counts with no associated toxicological findings.

Reproductive studies have been performed in pregnant cynomolgus monkeys receiving belimumab150 mg/kg body weight by intravenous infusion (approximately 9 times the anticipated maximum humanclinical exposure) every 2 weeks for up to 21 weeks, and belimumab treatment was not associated with director 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 andinfants and reversible reduction of IgM in infant monkeys. B cell numbers recovered after the cessation ofbelimumab treatment by about 1 year post-partum in adult monkeys and by 3 months of life in infantmonkeys; 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 studiesof belimumab at doses up to and including 50 mg/kg body weight. No treatment-related changes were notedin the male and female reproductive organs of sexually mature animals. An informal assessment of menstrualcycling in females demonstrated no belimumab-related changes.

As belimumab is a monoclonal antibody no genotoxicity studies have been conducted. No carcinogenicitystudies or fertility studies (male or female) have been performed.

Arginine hydrochloride

Histidine

Histidine monohydrochloride

Polysorbate 80 (E 433)

Sodium chloride

Water for injection

None known.

3 years.

Store in a refrigerator (2 °C to 8 °C).

Do not freeze.

Store in the original carton in order to protect from light.

A single Benlysta pre-filled syringe can be stored at temperatures up to a maximum of 25 °C for a period ofup to 12 hours. The pre-filled syringe must be protected from light, and discarded if not used within the12 hour period.

1 mL solution in a type 1 glass syringe with a fixed needle (stainless steel) and needle cap.

Available in pack of 1 pre-filled syringe and pack of 4 pre-filled syringes.

Not all pack sizes may be marketed.

Comprehensive instructions for subcutaneous administration of Benlysta in a pre-filled syringe are providedat the end of the package leaflet (see Step-by-step instructions).

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

GlaxoSmithKline (Ireland) Limited12 Riverwalk

Citywest Business Campus

Dublin 24

Ireland

EU/1/11/700/006 1 pre-filled syringe

EU/1/11/700/007 4 pre-filled syringes

Date of first authorisation: 13 July 2011

Date of latest renewal: 18 February 2016

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.