Article Contents
- 1. NAME OF THE MEDICINAL PRODUCT
- 2. QUALITATIVE AND QUANTITATIVE COMPOSITION
- 3. PHARMACEUTICAL FORM
- 4. CLINICAL PARTICULARS
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. PHARMACOLOGICAL PROPERTIES
- 6. PHARMACEUTICAL PARTICULARS
- 7. MARKETING AUTHORISATION HOLDER
- 8. MARKETING AUTHORISATION NUMBER(S)
- 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
- 10. DATE OF REVISION OF THE TEXT
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.
1.NAME OF THE MEDICINAL PRODUCT
Benlysta 120 mg powder for concentrate for solution for infusion.
Benlysta 400 mg powder for concentrate for solution for infusion.
2.QUALITATIVE AND QUANTITATIVE COMPOSITION
Benlysta 120 mg powder for concentrate for solution for infusion.
Each vial contains 120 mg of belimumab. After reconstitution, the solution contains 80 mg belimumab per ml.
Benlysta 400 mg powder for concentrate for solution for infusion.
Each vial contains 400 mg of belimumab. After reconstitution, the solution contains 80 mg belimumab per ml.
Belimumab is a human, IgG1λ monoclonal antibody, produced in a mammalian cell line (NS0) by recombinant DNA technology.
For the full list of excipients, see section 6.1.
3.PHARMACEUTICAL FORM
Powder for concentrate for solution for infusion.
White to
4.CLINICAL PARTICULARS
4.1Therapeutic indications
Benlysta is indicated as
4.2Posology 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
Patients treated with Benlysta should be made aware of the potential risk of severe or
Posology
Premedication including an antihistamine, with or without an antipyretic, may be administered before the infusion of Benlysta (see section 4.4).
The recommended dose regimen is 10 mg/kg Benlysta on Days 0, 14 and 28, and at
Special populations
Elderly (>65 years)
The efficacy and safety of Benlysta in the elderly has not been established. Data on patients >65 years are limited to <1.6% of the studied population. Therefore, the use of Benlysta in elderly patients is not recommended unless the benefits are expected to outweigh the risks. In case administration of Benlysta to elderly patients is deemed necessary, 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
The safety and efficacy of Benlysta in children and adolescents (less than 18 years of age) has 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
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
4.3Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4Special warnings and precautions for use
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
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 patients, and included anaphylactic reaction, bradycardia, hypotension, angioedema, and dyspnea. 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 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 (see section 4.8). Physicians should exercise caution when considering the use of Benlysta in patients with severe or chronic infections or a history of recurrent infection. Patients who develop an infection while undergoing treatment with Benlysta should be monitored closely and careful consideration given to interrupting immunosuppressant therapy including
belimumab until the infection is resolved. The risk of using Benlysta in patients with active or latent tuberculosis is unknown.
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. If PML is suspected, further dosing must be suspended until PML has been excluded.
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
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 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.
Sodium content
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium- free’.
4.5Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed.
4.6Fertility, 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. 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 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 every 2 weeks.
Because maternal antibodies (IgG) are excreted in breast milk, it is recommended that a decision should be made whether to discontinue
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).
4.7Effects 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 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.
4.8Undesirable effects
Summary of the safety profile
The safety of Benlysta in patients with SLE has been evaluated in 3
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. Data from postmarketing reports are also included.
Patients received Benlysta 10 mg/kg intravenously over a
The majority of patients were also receiving one or more of the following concomitant treatments for SLE: corticosteroids, immunomodulatory medicinal products,
Adverse reactions were reported in 93% of
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 |
Rare | >1/10,000 to <1/1000 |
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
System organ class | Frequency | Adverse reaction(s) |
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Infections and infestations | Very common | Bacterial infections, e.g. bronchitis, |
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| cystitis |
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| Common | Gastroenteritis viral, pharyngitis, |
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| nasopharyngitis |
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Blood and lymphatic system | Common | Leucopenia |
disorders |
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Immune system disorders | Common | Hypersensitivity reactions* |
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| Uncommon | Anaphylactic reaction, angioedema |
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| Rare | |
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| hypersensitivity reactions |
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Psychiatric disorders | Common | Depression, insomnia |
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Nervous system disorders | Common | Migraine |
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Gastrointestinal disorders | Very common | Diarrhoea, nausea |
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Skin and subcutaneous tissue | Uncommon | Urticaria, rash |
disorders |
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Musculoskeletal and | Common | Pain in extremity |
connective tissue disorders |
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General disorders and | Common | |
administration site conditions |
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*’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 dyspnea. ‘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 have been reported in patients treated with Benlysta. Some infections were severe or fatal.
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 [Body mass index (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.
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 the national reporting system listed in Appendix V.
4.9Overdose
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.
5.PHARMACOLOGICAL PROPERTIES
5.1Pharmacodynamic properties
Pharmacotherapeutic group: Selective immunosuppressants, ATC code: L04AA26
Mechanism of action
Benlysta is a human IgG1λ monoclonal antibody specific for soluble human B Lymphocyte Stimulator protein (BLyS, also referred to as BAFF and TNFSF13B). Benlysta blocks the binding of soluble BLyS, a B cell survival factor, to its receptors on B cells. Benlysta does not bind B cells directly, but by binding BLyS,
Benlysta inhibits the survival of B cells, including autoreactive B cells, and reduces the differentiation of B cells into
BLyS levels are elevated in patients with SLE and other autoimmune diseases. There is an association between plasma BLyS levels and SLE disease activity. The relative contribution of BLyS levels to the pathophysiology of SLE is not fully understood.
Pharmacodynamic effects
Changes in biomarkers were seen in clinical trials. In patients with hypergammaglobulinemia, normalization of IgG levels was observed by Week 52 in 49% and 20% of patients receiving Benlysta and placebo, respectively.
In patients with
In patients with low complement levels, normalization of C3 and C4 was observed by Week 52 in 38% and 44% of patients receiving Benlysta and in 17% and 19% of patients receiving placebo.
Of the
Changes in B cells (including naïve, memory and activated B cells, and plasma cells) and IgG levels occurring in patients during ongoing treatment with intravenous belimumab were followed in a
Immunogenicity
Assay sensitivity for neutralising antibodies and
Among
Clinical efficacy and safety
The efficacy of Benlysta was evaluated in 2 randomized,
classification criteria. Patients had active SLE disease, defined as a
consisting of (alone or in combination): corticosteroids,
Patients who had severe active lupus nephritis and patients who had severe active central nervous system (CNS) lupus were excluded.
At baseline 52% of patients had high disease activity (SELENA SLEDAI score >10), 59% of patients had mucocutaneous, 60% had musculoskeletal, 16% had haematological, 11% had renal and 9% had vascular organ domain involvement (BILAG A or B at baseline).
- Quixidar - Glaxo Group Ltd.
- Alisade - Glaxo Group Ltd.
- Agenerase - Glaxo Group Ltd.
Prescription drugs listed. Manufacturer: "Glaxo Group Ltd."
The primary efficacy endpoint was a composite endpoint (SLE Responder Index) that defined response as meeting each of the following criteria at Week 52 compared with baseline:
•
•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 organ system, or in the patient’s overall condition.
Table 1: Response rate at week 52
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| Pooled | |
| Placebo* | Benlysta | Placebo* | Benlysta | Placebo* |
| Benlysta |
Response | (n=275) | 10 mg/kg* | (n=287) | 10 mg/kg* | (n=562) |
| 10 mg/kg* |
| (n=273) |
| (n=290) |
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| (n=563) | |
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SLE responder | 33.8% | 43.2% | 43.6% | 57.6% | 38.8% |
| 50.6% |
index |
| (p=0.021) |
| (p=0.0006) |
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| (p<0.0001) |
Observed |
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difference vs |
| 9.4% |
| 14.0% |
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| 11.8% |
placebo |
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Odds ratio |
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(95% CI) vs |
| 1.52 |
| 1.83 |
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| 1.68 |
placebo |
| (1.07, 2.15) |
| (1.30,2.59) |
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| (1.32,2.15) |
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Components of | SLE responder | index |
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Percent of | 35.6% | 46.9% | 46.0% | 58.3% | 40.9% |
| 52.8% |
patients with |
| (p=0.006) |
| (p= 0.0024) |
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| (p<0.0001) |
reduction in |
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SELENA- |
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SLEDAI ≥4 |
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Percent of | 65.1% | 69.2% | 73.2% | 81.4% | 69.2% |
| 75.5% |
patients with |
| (p=0.32) |
| (p=0.018) |
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| (p=0.019) |
no worsening |
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by BILAG |
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index |
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Percent of | 62.9% | 69.2% | 69.3% | 79.7% | 66.2% |
| 74.6% |
patients with |
| (p=0.13) |
| (p=0.0048) |
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| (p=0.0017) |
no worsening |
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by PGA |
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* plus standard therapy/standard of care
In a pooled analysis of the two studies, the percentage of patients receiving >7.5 mg/day prednisone (or equivalent) at baseline, whose average corticosteroid dose was reduced by at least 25% to a dose equivalent to prednisone ≤7.5 mg/day during Weeks 40 through 52, was 17.9% in the group receiving Benlysta and 12.3% in the group receiving placebo (p=0.0451).
Flares in SLE were defined by the modified SELENA SLEDAI SLE Flare Index. The median time to the first flare was delayed in the pooled group receiving belimumab compared to the group receiving placebo (110 vs 84 days, hazard ratio=0.84, p=0.012). Severe flares were observed in 15.6% of the Benlysta group compared to 23.7% of the placebo group over the 52 weeks of observation (observed treatment difference = - 8.1%; hazard ratio=0.64, p=0.0011).
Benlysta demonstrated improvement in fatigue compared with placebo measured by the
Univariate and multivariate analysis of the primary endpoint in
Table 2: Patients with low complement and positive
Subgroup | ||
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Placebo | Benlysta | |
| (n=287) | 10 mg/kg |
|
| (n=305) |
SRI response rate at week 52 (%) | 31.7 | 51.5 (p<0.0001) |
Observed treatment difference vs placebo (%) |
| 19.8 |
SRI response rate (excluding complement and | 28.9 | 46.2 (p<0.0001) |
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Observed treatment difference vs placebo (%) |
| 17.3 |
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Severe flares over 52 weeks |
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Patients experiencing a severe flare (%) | 29.6 | 19.0 |
Observed treatment difference vs. placebo (%) |
| 10.6 |
Time to severe flare [Hazard ratio (95% CI)] |
| 0.61 (0.44, 0.85) |
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| (p=0.0038) |
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Prednisone reduction by ≥25% from baseline | (n=173) | (n=195) |
to ≤7.5 mg/day during weeks 40 through 52* | 12.1 | 18.5 (p=0.0964) |
(%) |
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Observed treatment difference vs placebo (%) |
| 6.3 |
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1.99 | 4.21 (p=0.0048) | |
baseline at |
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Observed treatment difference vs placebo |
| 2.21 |
(mean difference) |
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Placebo | Benlysta | |
| (n=131) | 10 mg/kg |
|
| (n=134) |
SRI response rate at | 27.5 | 39.6 (p=0.0160) |
Observed treatment difference vs placebo (%) |
| 12.1 |
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* Among patients with baseline prednisone dose >7.5 mg/day
Age and race
There were too few patients over 65 years of age, or black/African American patients enrolled in the controlled clinical trials to draw meaningful conclusions about the effects of age or race on clinical outcomes.
Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with Benlysta in one or more subsets of the paediatric population in SLE (see section 4.2 for information on paediatric use).
5.2Pharmacokinetic properties
The pharmacokinetic parameters quoted below are based on population parameter estimates for the 563 patients who received Benlysta 10 mg/kg in the two Phase III studies.
Absorption
Benlysta is administered by intravenous infusion. Maximum serum concentrations of belimumab were generally observed at, or shortly after, the end of the infusion. The maximum serum concentration was 313 µg/ml (range:
Distribution
Belimumab distributed to tissues with an overall volume of distribution of 5.29 litres.
Biotransformation
Belimumab is a protein for which the expected metabolic pathway is degradation to small peptides and individual amino acids by widely distributed proteolytic enzymes. Classical biotransformation studies have not been conducted.
Elimination
Serum belimumab concentrations declined in a
1.75 days and terminal
Special patient populations
Paediatric population: No pharmacokinetic data are available in paediatric patients.
Elderly (>65 years of age): Benlysta has been studied in a limited number of elderly patients. Within the overall SLE intravenous study population, age did not affect belimumab exposure in the population pharmacokinetic analysis. However, given the small number of subjects 65 years or older, an effect of age cannot be ruled out conclusively.
Renal impairment: No specific studies have been conducted to examine the effects of renal impairment on the pharmacokinetics of Benlysta. During clinical development Benlysta was studied in patients with SLE and renal impairment (261 subjects with moderate renal impairment, creatinine clearance ≥30 and
<60 ml/min; 14 subjects with severe renal impairment, creatinine clearance ≥15 and <30 ml/min). The reduction in systemic clearance estimated by population PK modelling for patients at the midpoints of the renal impairment categories relative to patients with median creatinine clearance in the PK population (79.9 ml/min) were 1.4% for mild (75 ml/min), 11.7% for moderate (45 ml/min) and 24.0% for severe (22.5 ml/min) renal impairment. Although proteinuria (> 2 g/day) increased belimumab clearance and
decreases in creatinine clearance decreased belimumab clearance, these effects were within the expected range of variability. 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 impairment on the pharmacokinetics of belimumab. IgG1 molecules such as belimumab are catabolised by widely distributed proteolytic enzymes, which are not restricted to hepatic tissue and changes in hepatic function are unlikely to have any effect on the elimination of belimumab.
Body weight/BMI:
5.3Preclinical safety data
Intravenous and subcutaneous administration to monkeys resulted in the expected reduction in the number of peripheral and lymphoid tissue B cell counts with no associated toxicological findings.
Reproductive studies have been performed in pregnant cynomolgus monkeys receiving belimumab 150 mg/kg by intravenous infusion (approximately 9 times the anticipated maximum human clinical exposure) every 2 weeks for up to 21 weeks, and Benlysta treatment was not associated with direct or indirect harmful effects with respect to maternal toxicity, developmental toxicity, or teratogenicity.
Effects on male and female fertility in monkeys were assessed in the
As belimumab is a monoclonal antibody no genotoxicity studies have been conducted. No carcinogenicity studies or fertility studies (male or female) have been performed.
6.PHARMACEUTICAL PARTICULARS
6.1List of excipients
Citric acid monohydrate (E330)
Sodium citrate (E331)
Sucrose
Polysorbate 80
6.2Incompatibilities
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.
6.3Shelf life
Unopened vials 5 years.
Reconstituted solution
After reconstitution with water for injections, the reconstituted solution, if not used immediately, should be protected from direct sunlight, and stored refrigerated at 2°C - 8°C.
Reconstituted and diluted solution for infusion
Solution of Benlysta diluted in sodium chloride 9 mg/ml (0.9%), sodium chloride 4.5 mg/ml (0.45%), or Lactated Ringer’s solution for injection may be stored at
The total time from reconstitution of Benlysta to completion of infusion should not exceed 8 hours.
6.4Special precautions for storage
Store in a refrigerator (2°C - 8°C).
Do not freeze.
Store in the original carton in order to protect from light.
For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.
6.5Nature and contents of container
Benlysta 120 mg powder for concentrate for solution for infusion
Type 1 glass vials (5 ml), sealed with a siliconised chlorobutyl rubber stopper and a
Pack size: 1 vial
Benlysta 400 mg powder for concentrate for solution for infusion
Type 1 glass vials (20 ml), sealed with a siliconised chlorobutyl rubber stopper and a
Pack size: 1 vial
6.6Special precautions for disposal and other handling
Preparation of 120 mg solution for infusion
Reconstitution
Reconstitution and dilution must be carried out under aseptic conditions.
Allow
It is recommended that a
The 120 mg
The stream of water for injections should be directed toward the side of the vial to minimize foaming. Gently swirl the vial for 60 seconds. Allow the vial to sit at room temperature (15°C - 25°C) during reconstitution,
gently swirling the vial for 60 seconds every 5 minutes until the powder is dissolved. Do not shake. Reconstitution is typically complete within 10 to 15 minutes after the water has been added, but it may take up to 30 minutes.
Protect the reconstituted solution from sunlight.
If a mechanical reconstitution device is used to reconstitute Benlysta it should not exceed 500 rpm and the vial should be swirled for no longer than 30 minutes.
Once reconstitution is complete, the solution should be opalescent and colorless to pale yellow and without particles. Small air bubbles, however, are expected and acceptable.
After reconstitution, a volume of 1.5 ml (corresponding to 120 mg belimumab) can be withdrawn from each vial.
Dilution
The reconstituted medicinal product is diluted to 250 ml with sodium chloride 9 mg/ml (0.9%), sodium chloride 4.5 mg/ml (0.45%), or Lactated Ringer’s solution for injection.
5% glucose intravenous solutions are incompatible with Benlysta and must not be used.
From a 250 ml infusion bag or bottle of sodium chloride 9 mg/ml (0.9%), sodium chloride 4.5 mg/ml (0.45%), or Lactated Ringer’s solution for injection, withdraw and discard a volume equal to the volume of the reconstituted Benlysta solution required for the patient’s dose. Then add the required volume of the reconstituted Benlysta solution into the infusion bag or bottle. Gently invert the bag or bottle to mix the solution. Any unused solution in the vials must be discarded.
Inspect the Benlysta solution visually for particulate matter and discoloration prior to administration. Discard the solution if any particulate matter or discoloration is observed.
The total time from reconstitution of Benlysta to completion of infusion should not exceed 8 hours.
Preparation of 400 mg solution for infusion
Reconstitution
Reconstitution and dilution must be carried out under aseptic conditions.
Allow
It is recommended that a
The 400 mg
The stream of water for injections should be directed toward the side of the vial to minimize foaming. Gently swirl the vial for 60 seconds. Allow the vial to sit at room temperature (15°C - 25°C) during reconstitution,
gently swirling the vial for 60 seconds every 5 minutes until the powder is dissolved. Do not shake.
Reconstitution is typically complete within 10 to 15 minutes after the water has been added, but it may take up to 30 minutes.
Protect the reconstituted solution from sunlight.
If a mechanical reconstitution device is used to reconstitute Benlysta it should not exceed 500 rpm and the vial should be swirled for no longer than 30 minutes.
Once reconstitution is complete, the solution should be opalescent and colorless to pale yellow and without particles. Small air bubbles, however, are expected and acceptable.
After reconstitution, a volume of 5 ml (corresponding to 400 mg belimumab) can be withdrawn from each vial.
Dilution
The reconstituted medicinal product is diluted to 250 ml with sodium chloride 9 mg/ml (0.9%), sodium chloride 4.5 mg/ml (0.45%), or Lactated Ringer’s solution for injection.
5% glucose intravenous solutions are incompatible with Benlysta and must not be used.
From a 250 ml infusion bag or bottle of sodium chloride 9 mg/ml (0.9%), sodium chloride 4.5 mg/ml (0.45%), or Lactated Ringer’s solution for injection, withdraw and discard a volume equal to the volume of the reconstituted Benlysta solution required for the patient’s dose. Then add the required volume of the reconstituted Benlysta solution into the infusion bag or bottle. Gently invert the bag or bottle to mix the solution. Any unused solution in the vials must be discarded.
Inspect the Benlysta solution visually for particulate matter and discoloration prior to administration. Discard the solution if any particulate matter or discoloration is observed.
The total time from reconstitution of Benlysta to completion of infusion should not exceed 8 hours.
Method of administration
Benlysta is infused over a 1 hour period.
Benlysta should not be infused concomitantly in the same intravenous line with other agents. No physical or biochemical compatibility studies have been conducted to evaluate the
No incompatibilities between Benlysta and polyvinylchloride or polyolefin bags have been observed.
Disposal
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7.MARKETING AUTHORISATION HOLDER
Glaxo Group Limited
980 Great West Road
Brentford
Middlesex TW8 9GS
United Kingdom
8.MARKETING AUTHORISATION NUMBER(S)
EU/1/11/700/001
EU/1/11/700/002
9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 13 July 2011
Date of latest renewal: 18 February 2016
10.DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu
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