1. Name Of The Medicinal Product
Benlysta®
Benlysta®
2. Qualitative And Quantitative Composition
Each vial contains 120 mg of belimumab. After reconstitution, the solution contains 80 mg belimumab per ml.
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 a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Powder for concentrate for solution for infusion.
White to off-white powder.
4. Clinical Particulars
4.1 Therapeutic Indications
Benlysta is indicated as add-on therapy in adult patients with active, autoantibody-positive systemic lupus erythematosus (SLE) with a high degree of disease activity (e.g positive anti
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 hypersensitivity reactions and infusion reactions. Therefore, Benlysta should be administered in an environment where resources for managing such reactions are immediately available.
There are no or insufficient data available on the effects of Benlysta in patients with severe active lupus nephritis or severe active central nervous system lupus. Therefore, Benlysta cannot be recommended to treat these conditions (see section 4.4).
Posology
Premedication including an antihistamine, with or without an antipyretic, may be administered before the infusion of Benlysta.
The recommended dose regimen is 10 mg/kg Benlysta on Days 0, 14 and 28, and at 4
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 (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 1
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 (see section 6.1).
4.4 Special 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 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. In the event of a severe reaction, Benlysta administration must be interrupted and appropriate medical therapy administered (see section 4.2).
Premedication including an antihistamine, with or without an antipyretic, may be administered before the infusion of Benlysta.
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).
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.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
No interaction studies have been performed.
4.6 Pregnancy And Lactation
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).
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 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.
4.8 Undesirable Effects
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
The majority of patients were also receiving one or more of the following concomitant treatments for SLE: corticosteroids, immunomodulatory medicinal products, anti
Adverse reactions were reported in 93% of Benlysta-treated patients and 92% of placebo-treated patients. The most frequently reported adverse reactions (
Tabulated list of adverse reactions
Adverse reactions are listed below by MedDRA system organ class and by frequency. The frequency categories used are:
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Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
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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.
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 2). None of these gastrointestinal events in obese patients were serious.
4.9 Overdose
There is no clinical experience with overdose of Benlysta.
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
5.1 Pharmacodynamic 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 immunoglobulin-producing plasma cells.
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 anti-dsDNA antibodies, 16% of patients treated with Benlysta converted to anti-dsDNA negative compared with 7% of the patients receiving placebo by Week 52.
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 anti-phospholipid antibodies, only anti-cardiolipin antibody was measured. For anti-cardiolipin IgA antibody a 37% reduction at Week 52 was seen (p=0.0003), for anti-cardiolipin IgG antibody a 26% reduction at Week 52 was seen (p=0.0324) and for anti-cardiolipin IgM a 25% reduction was seen (p=NS, 0.46).
A significant reduction of circulating B cells, including naïve, activated, plasma, and the SLE B cell subset was seen at Week 52.
Immunogenicity
Assay sensitivity for neutralising antibodies and non-specific anti
In the two Phase III studies, 4 out of 563 (0.7%) patients in the 10 mg/kg group and 27 out of 559 (4.8%) patients in the 1 mg/kg group tested positive for persistent presence of anti-belimumab antibodies.
Among persistent-positive subjects in the Phase III studies, 1/10 (10%), 2/27 (7%) and 1/4 (25%) subjects in the placebo, 1 mg/kg and 10 mg/kg groups, respectively, experienced infusion reactions on a dosing day; these infusion reactions were all non-serious and mild to moderate in severity. Few patients with ADA reported serious/severe AEs. The rates of infusion reactions among persistent-positive subjects were comparable to the rates for ADA negative patients of 75/552 (14%), 78/523 (15%), and 83/559 (15%) in the placebo, 1 mg/kg and 10 mg/kg groups, respectively.
Clinical efficacy and safety
The efficacy of Benlysta was evaluated in 2 randomized, double
Patients who had severe active lupus nephritis and patients who had severe active central nervous system (CNS) lupus were excluded.
BLISS-76 was conducted primarily in North America and Western Europe. Background medicinal products included corticosteroids (76%;>7.5 mg/day 46%), immunosuppressives (56%), and anti-malarials (63%).
BLISS-52 was conducted in South America, Eastern Europe, Asia, and Australia. Background medicinal products included corticosteroids (96%;>7.5 mg/day 69%), immunosuppressives (42%), and anti-malarials (67%).
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).
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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* 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 FACIT-Fatigue scale in the pooled analysis. The mean change of score at Week 52 from baseline is significantly greater with Benlysta compared to placebo (4.70 vs 2.46, p=0.0006).
Univariate and multivariate analysis of the primary endpoint in pre-specified subgroups demonstrated that the greatest benefit was observed in patients with higher disease activity including patients with SELENA SLEDAI scores
Post-hoc analysis has identified high responding subgroups such as those patients with low complement and positive anti-dsDNA at baseline, see Table 2. Of these patients, 64.5% had SELENA SLEDAI scores
Table 2: Patients with low complement and positive anti-dsDNA at baseline
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* Among patients with baseline prednisone dose >7.5 mg/day
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).
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.
5.2 Pharmacokinetic 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: 173-573 µg/ml) based on simulating the concentration time profile using the typical parameter values of the population pharmacokinetic model.
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 bi(range: 69-622 ml/day).
Paediatric population : No pharmacokinetic data are available in paediatric patients.
Elderly (older than or equal to 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 > 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: Weight-normalised belimumab dosing leads to decreased exposure for underweight subjects (BMI <18.5) and to increased exposure for obese subjects (BMI >30). BMI
No dose adjustment is recommended for underweight or obese subjects.
5.3 Preclinical Safety Data
Nonclinical data reveal no special hazard for humans based on studies of repeated dose toxicity and toxicity to reproduction.
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. Treatment-related findings were limited to the expected reversible reduction of B cells in both dams and infants and reversible reduction of IgM in infant monkeys. B cell numbers recovered after the cessation of belimumab treatment by about 1 year post-partum in adult monkeys and by 3 months of life in infant monkeys; IgM levels in infants exposed to belimumab in utero recovered by 6 months of age.
Effects on male and female fertility in monkeys were assessed in the 6-month repeat dose toxicology studies of belimumab at doses up to and including 50 mg/kg. No treatment-related changes were noted in the male and female reproductive organs of sexually mature animals. An informal assessment of menstrual cycling in females demonstrated no belimumab-related changes.
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
6.1 List Of Excipients
Citric acid monohydrate (E330)
Sodium citrate (E331)
Sucrose
Polysorbate 80
6.2 Incompatibilities
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.
6.3 Shelf Life
Unopened vials
3 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%) solution for injection may be stored at 2°C
The total time from reconstitution of Benlysta to completion of infusion should not exceed 8 hours.
6.4 Special Precautions For Storage
Unopened vials
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 of the reconstituted and diluted medicinal product, see section 6.3.
6.5 Nature And Contents Of Container
120 mg vial:
Type 1 glass vials (5 ml), sealed with a latex-free, siliconised chlorobutyl rubber stopper and a flip-off aluminum seal.
400 mg vial:
Type 1 glass vials (20 ml), sealed with a latex-free, siliconised chlorobutyl rubber stopper and a flip-off aluminum seal.
Pack size: 1 vial
6.6 Special Precautions For Disposal And Other Handling
Preparation of the solution for infusion
Reconstitution
Reconstitution and dilution must be carried out under aseptic conditions.
Allow 10-15 minutes for the vial to warm to room temperature (15°C - 25°C).
The 120 mg single-use vial of belimumab is reconstituted with 1.5 ml of water for injections to yield a final concentration of 80 mg/ml belimumab.
The 400 mg single-use vial of belimumab is reconstituted with 4.8 ml of sterile water for injections to yield a final concentration of 80 mg/ml belimumab.
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.
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%) 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%) 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 co-administration of Benlysta with other agents.
No incompatibilities between Benlysta and polyvinylchloride or polyolefin bags have been observed.
Disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7. Marketing Authorisation Holder
Glaxo Group Limited
Glaxo Wellcome House
Berkeley Avenue
Greenford
Middlesex UB6 0NN
United Kingdom
8. Marketing Authorisation Number(S)
EU/1/11/700/001 - Benlysta 120 mg - Powder for concentrate for solution for infusion
EU/1/11/700/002 - Benlysta 400 mg - Powder for concentrate for solution for infusion
9. Date Of First Authorisation/Renewal Of The Authorisation
13/07/2011
10. Date Of Revision Of The Text
13/07/2011
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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