Chemical formula: C₆₇₁₄H₁₀₄₂₈O₂₁₀₂S₅₂
Belimumab interacts in the following cases:
Live vaccines should not be given for 30 days before, or concurrently with belimumab, 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 belimumab.
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 belimumab 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 belimumab does not significantly affect the ability to maintain a protective immune response to immunisations received prior to administration of belimumab. 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 belimumab. 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.
Belimumab has not been studied in combination with other B cell targeted therapy or intravenous cyclophosphamide. Caution should be exercised if belimumab is co-administered with other B cell targeted therapy or cyclophosphamide.
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).
In controlled clinical intravenous and subcutaneous studies, psychiatric disorders (depression, suicidal ideation and behaviour including suicides) have been reported more frequently in patients receiving belimumab. Physicians should assess the risk of depression and suicide considering the patient’s medical history and current psychiatric status before treatment with belimumab 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.
Progressive multifocal leukoencephalopathy (PML) has been reported with belimumab treatment for SLE. Physicians should be particularly alert to symptoms suggestive of PML that patients may not notice (e.g., cognitive, neurological or psychiatric symptoms or signs). Patients should be monitored for any of these new or worsening symptoms or signs, and if such symptoms/signs occur, referral to a neurologist and appropriate diagnostic measures for PML should be considered. If PML is suspected, further dosing must be suspended until PML has been excluded.
Administration of subcutaneous or intravenous belimumab may result in hypersensitivity reactions which can be severe, and fatal. In the event of a severe reaction, belimumab administration must be interrupted and appropriate medical therapy administered. The risk of hypersensitivity reactions is greatest with the first two doses; however the risk should be considered for every administration. Patients with a history of multiple drug allergies or significant hypersensitivity may be at increased risk. Recurrence of clinically significant reactions after initial appropriate treatment of symptoms has also been observed.
Patients should be advised that hypersensitivity reactions are possible, on the day of, or several days after administration, 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 available to the patient. Delayed-type, non-acute hypersensitivity reactions have also been 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.
The mechanism of action of belimumab could increase the risk for the development of infections, including opportunistic infections. Severe infections, including fatal cases, have been reported in SLE patients receiving immunosuppressant therapy, including belimumab. Physicians should exercise caution when considering the use of belimumab in patients with severe or chronic infections or a history of recurrent infection. Patients who develop an infection while undergoing treatment with belimumab should be monitored closely and careful consideration given to interrupting immunosuppressant therapy including belimumab until the infection is resolved. The risk of using belimumab in patients with active or latent tuberculosis is unknown.
Belimumab has not been studied in the following patient groups and is not recommended in:
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 must use effective contraception during belimumab treatment and for at least 4 months after the last treatment.
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.
The safety of belimumab in patients with SLE has been evaluated in 3 pre-registration, placebo-controlled intravenous studies, 1 placebo-controlled subcutaneous study, and one post-marketing, placebo-controlled intravenous study.
The data presented below reflect exposure to belimumab administered (10 mg/kg intravenously over a 1-hour period on Days 0, 14, 28, and then every 28 days for up to 52 weeks) in 674 patients with SLE, including 472 exposed for at least 52 weeks, and 556 patients exposed to 200 mg belimumab subcutaneously once weekly for up to 52 weeks. The safety data presented include data beyond Week 52 in some patients. 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 87% of belimumab-treated patients and 90% of placebo-treated patients. The most frequently reported adverse reactions (≥5% of patients with SLE treated with belimumab plus standard of care and at a rate ≥1% greater than placebo) were viral upper respiratory tract infections, bronchitis, and diarrhoea. The proportion of patients who discontinued treatment due to adverse reactions was 7% for belimumab-treated patients and 8% for placebo-treated patients.
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
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.
Very common: Bacterial infections, e.g. bronchitis, urinary tract infection
Common: Gastroenteritis viral, pharyngitis, nasopharyngitis, viral upper respiratory tract infection
Common: Leucopenia
Common: Hypersensitivity reactions*
Uncommon: Anaphylactic reaction
Rare: Delayed-type, non-acute hypersensitivity reactions
Common: Depression
Uncommon: Suicidal behaviour, suicidal ideation
Common: Migraine
Very common: Diarrhoea, nausea
Common: Injection site reactions**
Uncommon: Angioedema, urticaria, rash
Common: Pain in extremity
Common: Infusion or injection-related systemic 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 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 reactions in all cases.
** Applies to subcutaneous formulation only.
Data presented below are pooled from the intravenous clinical studies (10 mg/kg intravenous dose only) and the subcutaneous clinical study. Psychiatric disorders also includes data from a post-marketing study.
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.
The overall incidence of infections in intravenous and subcutaneous 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.
In the pre-registration intravenous clinical studies, serious psychiatric events were reported in 1.2% (8/674) of patients receiving belimumab 10 mg/kg 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 and 0.3% (2/675) of patients receiving placebo. There were two suicides in belimumab-treated patients (including one receiving 1 mg/kg belimumab).
In a randomised, double-blind, placebo-controlled, post-marketing study with belimumab 10 mg/kg administered intravenously, 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 studies did not exclude patients with a history of psychiatric disorders.
In the subcutaneous 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.
The incidence of leucopenia reported as an adverse event was 3% in the group receiving belimumab and 2% in the group receiving placebo.
In the subcutaneous trial, 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.
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