4.1. Therapeutic indications

Benlysta is indicated as add-on therapy in patients aged 5 years and older 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).

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

Posology

Premedication including an antihistamine, with or without an antipyretic, may be administered before the infusion of Benlysta (see section 4.4).

In patients with SLE or active lupus nephritis, 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.

In patients with SLE, discontinuation of treatment with Benlysta should be considered if there is no improvement in disease control after 6 months of treatment.

In patients with active lupus nephritis, Benlysta should be used in combination with corticosteroids and mycophenolate or cyclophosphamide for induction, or mycophenolate or azathioprine for maintenance.

Transition from intravenous to subcutaneous administration

SLE

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

Lupus nephritis

If a patient with lupus nephritis is being transitioned from Benlysta intravenous administration to subcutaneous administration, the first dose of 200 mg subcutaneous injection should be administered 1 to 2 weeks after the last intravenous dose. This transition should occur any time after the patient completes the first 2 intravenous doses (see section 5.2).

Special populations

Elderly

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).

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

SLE

The recommended dose regimen for children aged 5 years and older is 10 mg/kg Benlysta on Days 0, 14 and 28, and at 4-week intervals thereafter.

The safety and efficacy of Benlysta in children aged below 5 years have not been established. No data are available.

Lupus nephritis

The safety and efficacy of Benlysta in children and adolescents aged below 18 years with severe active lupus nephritis have 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

Traceability

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

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

• severe active central nervous system lupus (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

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

Infusion reactions and hypersensitivity

Administration of Benlysta may result in hypersensitivity reactions and infusion reactions which can be severe, and 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 knowledge to determine whether premedication could diminish the frequency or severity of infusion reactions.

In clinical studies, serious infusion and hypersensitivity reactions affected approximately 0.9 % of adult 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 sections 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 several days 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 belimumab could increase the risk for the development of infections in adults and children with lupus, including opportunistic infections, and younger children may be at increased risk. In controlled clinical studies, the incidence of serious infections was similar across the Benlysta and placebo groups; 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 before initiating Benlysta treatment. Benlysta should not be initiated in patients with active serious infections (including serious chronic infections). Physicians should exercise caution and carefully assess if the benefits are expected to outweigh the risks when considering the use of Benlysta in patients with a history of recurrent infection. Physicians should advise patients to contact their health care provider if they develop symptoms of an infection. Patients who develop an infection while undergoing treatment with Benlysta should be 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 latent tuberculosis is unknown.

Depression and suicidality

In controlled clinical intravenous and subcutaneous studies, psychiatric disorders (depression, suicidal ideation 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's medical history and current psychiatric status before treatment with Benlysta and continue to monitor patients during treatment. Physicians should advise patients (and caregivers where appropriate) to contact their health care provider about new or worsening psychiatric symptoms. In patients who experience such symptoms, treatment discontinuation should be considered.

Severe cutaneous adverse reactions

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which can be life-threatening or fatal, have been reported in association with Benlysta treatment. Patients should be advised of the signs and symptoms of SJS and TEN and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, Benlysta should be withdrawn immediately, and an alternative treatment should be considered. If the patient has developed SJS or TEN with the use of Benlysta, treatment with Benlysta must not be restarted in this patient at any time

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 as clinically indicated. If PML is suspected, immunosuppressant therapy, including Benlysta, must be suspended until PML has been excluded. If PML is confirmed, immunosuppressant therapy, including belimumab, must be discontinued.

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. However, in a small study evaluating the response to a 23-valent pneumococcal vaccine, overall immune responses to the different serotypes were similar in SLE patients receiving Benlysta compared with those receiving standard immunosuppressive treatment at the time of vaccination. There are insufficient data to draw conclusions regarding response to other vaccines.

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.

Malignancies and lymphoproliferative disorders

Immunomodulatory medicinal products, including Benlysta, may increase the risk of malignancy. Caution should be exercised when considering Benlysta 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.

Polysorbate 80 content

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

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially 'sodium-free'. However, as Benlysta powder for concentrate is diluted in a solution for infusion that contains sodium, this is to be taken into consideration for patients on a controlled sodium diet (see section 6.6).

4.5. Interaction with other medicinal products and other forms of interaction

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

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in males and females

Women of childbearing 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. Post-marketing data from a prospective pregnancy registry have collected pregnancy information in women exposed to belimumab. Due to the small sample size achieved, no definitive conclusions from this registry can be made regarding a potential risk of birth defects following exposure to belimumab.

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 the potential benefit justifies the potential risk to the foetus.

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 belimumab 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 belimumab. 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 in adults

The safety of belimumab in patients with SLE has been evaluated in three pre‑registration placebo‑controlled intravenous studies and one subsequent regional placebo-controlled intravenous study, one placebo‑controlled subcutaneous study, and two post‑marketing placebo‑controlled intravenous studies; the safety in patients 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 from the three pre-registration clinical studies and 470 patients in the subsequent placebo-controlled study with SLE administered Benlysta intravenously (10 mg/kg over a 1-hour period on Days 0, 14, 28, and then every 28 days for up to 52 weeks), and 556 patients with SLE exposed to Benlysta subcutaneously (200 mg once weekly 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 Benlysta intravenously (10 mg/kg for up to 104 weeks). Data from post-marketing reports are also included.

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 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 plus standard of care and at a rate ≥ 1 % greater than placebo) was nasopharyngitis. The proportion of patients who discontinued treatment due to adverse reactions was 7 % for Benlysta-treated patients and 8 % for placebo-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 herpes zoster. 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).

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

Not known

≥ 1/10

≥ 1/100 to < 1/10

≥ 1/1000 to < 1/100

≥ 1/10 000 to < 1/1000

cannot be estimated from the available data.

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

System organ class

Frequency

Adverse reaction(s)

Infections and infestations1

Very common

Bacterial infections, e.g. bronchitis, urinary tract infection

Common

Gastroenteritis viral, pharyngitis, nasopharyngitis, viral upper respiratory tract infection

Blood and lymphatic system disorders

Common

Leucopenia

Immune system disorders

Common

Hypersensitivity reactions2

Uncommon

Anaphylactic reaction

Rare

Delayed-type, non-acute hypersensitivity reactions

Psychiatric disorders

Common

Depression

Uncommon

Suicidal behaviour, suicidal ideation

Nervous system disorders

Common

Migraine

Gastrointestinal disorders

Common

Diarrhoea, nausea

Skin and subcutaneous tissue disorders

Common

Injection site reactions3, urticaria, rash

Uncommon

Angioedema

Not known

Stevens-Johnson syndrome, toxic epidermal necrolysis

Musculoskeletal and connective tissue disorders

Common

Pain in extremity

General disorders and administration site conditions

Common

Infusion or injection-related systemic reactions2, pyrexia

1 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 of symptoms including hypotension, angioedema, urticaria or other rash, pruritus, and dyspnoea. 'Infusion or injection-related systemic 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 or injection-related systemic reactions in all cases.

3 Applies to subcutaneous formulation only.

Description of selected adverse reactions

Data presented below are pooled from the three pre-registration intravenous clinical studies (10 mg/kg 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 systemic reactions and hypersensitivity were generally observed on the day of administration, but acute hypersensitivity reactions may also occur several days after dosing. Patients with a history of multiple drug allergies or significant hypersensitivity reactions may be at increased risk.

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

Infections: The overall incidence of infections in intravenous and subcutaneous pre-registration SLE studies was 63 % in both groups receiving Benlysta or placebo. Infections occurring in at least 3 % of patients receiving Benlysta and at least 1 % more frequently than patients receiving placebo were viral upper respiratory 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 for 0.4 % and 0 % of these, respectively. Infections leading to discontinuation of treatment occurred in 0.7 % of patients 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 section below.

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

In a randomised, double-blind, 52-week, post-marketing safety SLE study (BEL115467) which assessed mortality and specific adverse events in adults, serious infections occurred in 3.7 % of patients receiving Benlysta (10 mg/kg intravenously) vs. 4.1 % of patients receiving placebo. However, fatal infections (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 treatment with Benlysta.

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

In a post-marketing SLE study, serious psychiatric events were reported in 1.0 % (20/2002) of patients receiving Benlysta and 0.3 % (6/2001) of patients receiving placebo. Serious depression was reported in 0.3 % (7/2002) of patients receiving Benlysta and < 0.1 % (1/2001) of patients receiving placebo. The overall 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 in either 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 patients receiving 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 the group receiving Benlysta and 2 % in the group receiving placebo.

Gastrointestinal disorders: Obese patients [Body mass index (BMI) > 30 kg/m2] with SLE treated with intravenously administered 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.

Paediatric population

The adverse reaction profile in paediatric patients is based on 52-week safety data from a placebo-controlled study in which 53 patients (6 to 17 years of age) with SLE received Benlysta (10 mg/kg intravenously on Days 0, 14, 28, and then every 28 days, on a background of concomitant treatments). No new safety signals were observed in the paediatric population 12 years of age and above (n = 43). Safety data in children younger than 12 years of age (n = 10) are limited.

Infections

5- to 11-year-old group: infections were reported in 8/10 patients receiving Benlysta and 3/3 patients receiving placebo, and serious infections were reported in 1/10 patients receiving Benlysta 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 and 25/37 patients receiving placebo, and serious infections were reported in 3/43 patients receiving Benlysta and 3/37 patients receiving placebo. In the open-label extension phase there was one fatal infection in a patient receiving Benlysta.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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

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.