Belimumab

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).

Caution is recommended in patients with severe renal impairment due to the lack of data.

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

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.

Physicians should exercise caution and carefully assess if the benefits are expected to outweigh the risks when considering the use of belimumab in patients with a history of recurrent infection.

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

• severe active central nervous system lupus
• severe active lupus nephritis
• 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.

There are a limited amount of data from the use of belimumab 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.

Belimumab should not be used during pregnancy unless the potential benefit justifies the potential risk to the foetus.

It is unknown whether belimumab 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 belimumab therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Women of childbearing potential/Contraception in males and females

Women of childbearing potential must use effective contraception during belimumab treatment and for at least 4 months after the last treatment.

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.

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 belimumab 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 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 belimumab intravenously (10 mg/kg body weight 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 belimumab 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 belimumab intravenously (10 mg/kg body weight 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 belimumab-treated patients and 87% of placebo-treated patients. The most frequently reported adverse reaction (≥5% of patients with SLE treated with belimumab 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 belimumab-treated patients and 8% for placebo-treated patients.

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

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 ≥1/1000 to <1/100, Rare ≥1/10 000 to <1/1000.

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

¹ See 'Description of selected adverse reactions' 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 body weight 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 belimumab and 10% in the group receiving placebo, 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 of subcutaneous administration was 7% in the group receiving belimumab and 9% in the group receiving placebo. Clinically significant hypersensitivity reactions associated with belimumab administered subcutaneously and requiring permanent treatment discontinuation were reported in 0.2% of patients receiving belimumab and in no patients receiving placebo.

Infections

The overall incidence of infections in intravenous and subcutaneous pre-registration SLE studies was 63% in both groups receiving belimumab or placebo. Infections occurring in at least 3% of patients receiving belimumab 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 belimumab 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 belimumab 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 and the overall incidence of infections was 82% in patients receiving belimumab compared with 76% in patients receiving placebo. Serious infections occurred in 13.8% of patients receiving belimumab and in 17.0% of patients receiving placebo. Fatal infections occurred in 0.9% (2/224) of patients receiving belimumab 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 belimumab (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 belimumab-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 belimumab.

Psychiatric disorders

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

In a post-marketing SLE study, serious psychiatric events were reported in 1.0% (20/2002) of patients receiving belimumab and 0.3% (6/2001) of patients receiving placebo. Serious depression was reported in 0.3% (7/2002) of patients receiving belimumab 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 belimumab 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 belimumab 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 belimumab 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 belimumab and placebo, respectively. These injection site reactions (most commonly pain, erythema, hematoma, pruritus and induration) were mild to moderate in severity. The majority did not necessitate drug discontinuation.

Gastrointestinal disorders

Obese patients [Body mass index (BMI) >30 kg/m²] with SLE treated with intravenously administered belimumab 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 one subcutaneous study and one intravenous study.

In a 52-week open-label study in which 25 paediatric patients (10 to 17 years of age) with SLE received subcutaneous belimumab at a comparable exposure to adults (200 mg at a set dosing interval based on body weight), on a background of concomitant treatments, the safety profile in paediatric patients receiving belimumab 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 belimumab (10 mg/kg body weight 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 belimumab intravenously and 3/3 patients receiving placebo, and serious infections were reported in 1/10 patients receiving belimumab intravenously and ⅔ patients receiving placebo.

12- to 17-year-old group

Infections were reported in 22/43 patients receiving belimumab intravenously and 25/37 patients receiving placebo, and serious infections were reported in 3/43 patients receiving belimumab intravenously and 3/37 patients receiving placebo. In the open-label extension phase there was one fatal infection in a patient receiving belimumab intravenously.