Benlysta 120 mg and 400 mg powder for concentrate for solution for infusion Ref.[2540] Active ingredients: Belimumab

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).

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.

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.

No interaction studies have been performed.

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).

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.

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. 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 ≥ 1/10
Common ≥1/100 to <1/10
Uncommon ≥1/1,000 to <1/100

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

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

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 were reported in three patients treated with Benlysta. In one case, the causal relationship is unlikely. No opportunistic infections were reported in the placebo group.

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.

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.