Nulojix

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 
 
  



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1. NAME OF THE MEDICINAL PRODUCT 
 
NULOJIX 250 mg powder for concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each vial contains 250 mg of belatacept. 
After reconstitution, each ml of concentrate contains 25 mg belatacept. 
 
Belatacept is a fusion protein produced in Chinese hamster ovary cells by recombinant DNA 
technology. 
 
Excipient with known effect  
Each vial contains 0.65 mmol sodium. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder for concentrate for solution for infusion (powder for concentrate). 
 
The powder is a white to off-white whole or fragmented cake. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
NULOJIX, in combination with corticosteroids and a mycophenolic acid (MPA), is indicated for 
prophylaxis of graft rejection  in adults receiving a renal transplant (see section 5.1 for data on renal 
function). It is recommended to add an interleukin (IL)-2 receptor antagonist for induction therapy to 
this belatacept-based regimen. 
 
4.2 Posology and method of administration 
 
Treatment should be prescribed and supervised by specialist physicians experienced in the 
management of immunosuppressive therapy and of renal transplant patients. 
 
Belatacept has not been studied in patients with Panel Reactive Antibody (PRA) > 30% (who often 
require increased immunosuppression). Because of the risk of a high total burden of 
immunosuppression, belatacept should only be used in these patients after consideration of alternative 
therapy (see section 4.4).  
 
Posology 
 
The recommended dose is based on patient body weight (kg). The dose and treatment frequency is 
given below. 
 



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Table 1:  Dose of belatacept for renal transplant recipients 

Initial phase Dose 

Day of transplantation, prior to implantation (Day 1) 10 mg/kg 

Day 5, Day 14 and Day 28  10 mg/kg 

End of Week 8 and Week 12 after transplantation 10 mg/kg 

Maintenance phase Dose 

Every 4 weeks (± 3 days), starting at the end of week 16 after transplantation 5 mg/kg 
 
For more details on the dose calculation, see section 6.6. 
 
Patients do not require pre-medication prior to administration of belatacept. 
 
NULOJIX should be administered in combination with basiliximab induction, mycophenolate mofetil, 
and corticosteroids. Corticosteroid tapering in patients taking belatacept should be implemented 
cautiously, particularly in patients with 4 to 6 human leukocyte antigen (HLA) mismatches (see 
sections 4.4 and 5.1) 
 
Infusion-related reactions have been reported with belatacept administration in clinical studies. If any 
serious allergic or anaphylactic reaction occurs, belatacept therapy should be discontinued 
immediately and appropriate therapy initiated (see section 4.4). 
 
Therapeutic monitoring of belatacept is not required. 
 
During clinical studies, there was no dose modification of belatacept for a change in body weight of 
less than 10%. 
 
Special populations 
 
Elderly patients 
No dose adjustment is required (see sections 5.1 and 5.2). 
 
Renal impairment 
No dose adjustment is recommended in patients with renal impairment or undergoing dialysis (see 
section 5.2). 
 
Hepatic impairment 
No patients with hepatic impairment were studied in renal transplant protocols, therefore dose 
modification of belatacept in hepatic impairment can not be recommended.  
 
Paediatric population 
The safety and efficacy of belatacept in children and adolescents 0 to 18 years of age have not yet 
been established. No data are available.  
 
Method of administration 
NULOJIX is for intravenous use only. 
 
The diluted solution must be administered as an intravenous infusion at a relatively constant rate over 
30 minutes. Infusion of the first dose should be given in the immediate preoperative period or during 
surgery, but before completion of the transplant vascular anastomoses.  
 
For instructions on reconstitution and dilution of the medicinal product before administration, see 
section 6.6. 
 



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4.3 Contraindications 
 
Transplant recipients who are Epstein-Barr virus (EBV) seronegative or serostatus unknown. 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see 
section 4.4). 
 
4.4 Special warnings and precautions for use  
 
Post-transplant lymphoproliferative disorder (PTLD)  
In the Phase 2 and 3 studies (3 studies), the incidence of PTLD was higher in belatacept-treated 
patients than in ciclosporin-treated patients (see section 4.8). Belatacept-treated transplant recipients 
who are EBV seronegative are at an increased risk for PTLD compared with those who are EBV 
positive (see section 4.8). EBV serology should be ascertained before starting administration of 
belatacept. Transplant recipients who are EBV seronegative or serostatus unknown should not receive 
belatacept (see section 4.3). 
 
In addition to EBV seronegative status, other known risk factors for PTLD include cytomegalovirus 
(CMV) infection and T-cell-depleting therapy, which was more commonly used to treat acute rejection 
in belatacept-treated patients in Phase 3 clinical studies (see section 5.1). 
 
PTLD in belatacept-treated patients most often presented in the central nervous system (CNS). 
Physicians should consider PTLD in the differential diagnosis in patients with new or worsening 
neurologic, cognitive or behavioural signs or symptoms. 
 
Infections 
Use of immunosuppressants, including belatacept, can increase susceptibility to infection, including 
fatal infections, opportunistic infections, tuberculosis, and herpes (see progressive multifocal 
leukoencephalopathy (PML) warning below and also section 4.8). 
 
CMV prophylaxis is recommended for at least 3 months after transplantation, particularly for patients 
at increased risk for CMV infection. Pneumocystis pneumonia prophylaxis is recommended for at 
least 6 months following transplantation. 
 
Tuberculosis was more frequently observed in patients receiving belatacept than ciclosporin in clinical 
studies (see section 4.8). The majority of cases of tuberculosis occurred in patients who currently live 
or previously lived in countries with a high prevalence of tuberculosis. Patients should be evaluated 
for tuberculosis and tested for latent infection prior to initiating belatacept. Adequate treatment of 
latent tuberculosis infection should be instituted prior to belatacept use. 
 
Progressive multifocal leukoencephalopathy  
PML is a rare, often rapidly progressive and fatal, opportunistic infection of the CNS that is caused by 
the John Cunningham (JC) virus. In clinical studies with belatacept, 2 cases of PML were reported in 
patients receiving belatacept at doses higher than the recommended regimen. In the renal transplant 
studies of belatacept, one case of PML was reported in a patient who received an IL-2 receptor 
antagonist, mycophenolate mofetil (MMF) and corticosteroids as concomitant treatment. In the liver 
transplant study, the patient received MMF and corticosteroids as concomitant treatment. As an 
increased risk of PML and of other infections has been associated with high levels of overall 
immunosuppression, the recommended doses of belatacept and concomitant immunosuppressives, 
including MMF or MPA, should not be exceeded (see section 4.5). 
 
Early diagnosis and treatment may mitigate the impact of PML. Physicians should consider PML in 
the differential diagnosis in patients with new or worsening neurologic, cognitive or behavioural signs 
or symptoms. PML is usually diagnosed by brain imaging, including magnetic resonance imaging 
(MRI) or computed tomography (CT) scan, and cerebrospinal fluid (CSF) testing for JC viral DNA by 
polymerase chain reaction (PCR). When the clinical suspicion for PML is high, brain biopsy should be 



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considered in subjects if the diagnosis of PML cannot be established via CSF PCR and neuroimaging. 
Consultation with a neurologist is recommended for any suspected or confirmed cases of PML. 
 
If PML is diagnosed, reduction or withdrawal of immunosuppression is recommended taking into 
account the risk to the graft. Plasmapheresis may accelerate removal of belatacept. 
 
Malignancies 
In addition to PTLD, patients receiving immunosuppressive regimens, including belatacept, are at 
increased risk of malignancies, including skin cancer (see section 4.8). Exposure to sunlight and 
ultraviolet (UV) light should be limited by wearing protective clothing and using a sunscreen with a 
high protection factor. 
 
Graft thrombosis 
In clinical trials, an increased incidence of graft thrombosis was observed in the post-transplant period 
in recipients of extended criteria donor allografts. In postmarketing experience in patients with other 
predisposing risk factors for thrombosis of the renal allograft, renal allograft thrombosis has occurred 
when the initial dose of anti-thymocyte globulin, as immunosuppressive induction, was 
coadministered at the same or nearly the same time with the first dose of belatacept. (see section 4.8). 
 
Liver transplantation 
The safety and efficacy of belatacept have not been established in liver transplant patients, and 
therefore such use is not recommended. In a single Phase 2 clinical study in de novo liver transplant 
patients, an increase in the number of deaths was observed in 2 of 3 belatacept-containing regimens 
studied. These belatacept dosing regimens differed from those studied in renal transplant recipients 
(see section 5.1). 
 
Concomitant use with other immunosuppressive agents 
Belatacept has been administered with the following immunosuppressive agents in clinical studies: 
basiliximab, an MPA and corticosteroids. 
 
Lymphocyte Depleting Therapies and MPA: As the total burden of immunosuppression is a risk factor 
for malignancies and opportunistic infections, higher than the recommended doses of concomitant 
immunosuppressive agents should be avoided. Lymphocyte depleting therapies to treat acute rejection 
should be used cautiously.  
Patients with high PRA often require increased immunosuppression. Belatacept has not been studied 
in patients with PRA > 30% (see section 4.2). 
 
Corticosteroid Taper: Corticosteroid tapering in patients taking belatacept should be implemented 
cautiously, particularly in patients at high immunologic risk, such as those with 4 to 6 human 
leukocyte antigen (HLA) mismatches. In postmarketing experience, use of belatacept in conjunction 
with basiliximab induction, mycophenolate mofetil and corticosteroid taper to 5 mg/day by Week 6 
post-transplant was associated with an increased rate of acute rejection, particularly Grade III 
rejection. These Grade III rejections occurred in patients with 4 to 6 HLA mismatches (see sections 
4.2 and 5.1). 
 
For patients who may be switched from belatacept to another immunosuppressant, physicians should 
be aware of the 8-10 day half-life of belatacept to avoid potential under- or over-immunosuppression 
following discontinuation of belatacept.  
 
Allergic reactions 
Infusion-related reactions have been reported with belatacept administration in the clinical studies. 
Patients are not required to be pre-treated to prevent allergic reactions (see section 4.8). Special 
caution should be exercised in patients with a history of allergic reactions to belatacept or to any of the 
excipients. Anaphylaxis has been reported during post marketing surveillance (see section 4.8). If any 
serious allergic or anaphylactic reaction occurs, NULOJIX therapy should be discontinued 
immediately and appropriate therapy initiated. 
 



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Vaccinations 
Immunosuppressant therapy may affect response to vaccination. Therefore, during treatment with 
belatacept, vaccinations may be less effective although this has not been studied in clinical trials. The 
use of live vaccines should be avoided (see section 4.5). 
 
Autoimmune process 
There is a theoretical concern that treatment with belatacept might increase the risk of autoimmune 
processes (see section 4.8). 
 
Immunogenicity 
Although there were few patients that developed antibodies and there was no apparent correlation of 
antibody development to clinical response or adverse events, the data are too limited to make a 
definitive assessment (see section 4.8). 
The safety and efficacy of retreatment with belatacept has not been studied. The potential impact of 
pre-existing antibodies to belatacept should be taken into account when considering retreatment with 
belatacept following prolonged discontinuation, particularly in patients who have not received 
continuous immunosuppression. 
 
Patients on controlled sodium diet 
This medicinal product contains 0.65 mmol or 15 mg sodium per vial. This corresponds to 1.95 mmol 
(or 45 mg) sodium per maximum dose of 3 vials. This should be taken into consideration when 
treating patients on a controlled sodium diet. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Belatacept is a fusion protein that is not expected to be metabolised by the cytochrome P450 enzymes 
(CYPs) and UDP-glucuronosyltransferases (UGTs).  Belatacept appears not to have any relevant 
direct effects on cytokine levels in liver transplant recipients or in healthy volunteers. Belatacept is 
therefore not expected to affect cytochrome P450 enzymes via effects on cytokines. 
 
Belatacept is not expected to interrupt the enterohepatic recirculation of MPA. At a given dose of 
MMF, MPA exposure is approximately 40% higher with belatacept coadministration than with 
ciclosporin coadministration. 
 
Immunosuppressant therapy may affect response to vaccination. Therefore, during treatment with 
belatacept, vaccinations may be less effective although this has not been studied in clinical trials. The 
use of live vaccines should be avoided (see section 4.4). 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential/Contraception in males and females 
Women of childbearing potential should use effective contraception during treatment with belatacept 
and up to 8 weeks after the last dose of treatment since the potential risk to embryonic/foetal 
development is unknown. 
 
Pregnancy 
There are no adequate data from use of belatacept in pregnant women. Animal studies do not indicate 
direct or indirect harmful effects with respect to embryonal/foetal development at doses up to 16-fold 
and 19-fold a human 10 mg/kg dose based on AUC. In a pre- and postnatal development study in rats, 
limited changes in immune function were observed at 19-fold a human 10 mg/kg dose based on AUC 
(see section 5.3). Belatacept should not be used in pregnant women unless clearly necessary. 
 
Breast-feeding 
Studies in rats have shown excretion of belatacept in milk. It is unknown whether belatacept is 
excreted in human milk (see section 5.3). Women should not breast-feed while on treatment with a 
belatacept-based regimen. 
 



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Fertility 
There are no data on use of belatacept and effect on fertility in humans. In rats, belatacept had no 
undesirable effects on male or female fertility (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
Belatacept has a minor influence on the ability to drive and use machines since it may cause fatigue, 
malaise and/or nausea. Patients should be instructed that if they experience these symptoms they 
should avoid potentially hazardous tasks such as driving or operating machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
The adverse reaction profile associated with immunosuppressive agents is often difficult to establish 
due to the underlying disease and the concurrent use of multiple medicinal products. 
 
The most common serious adverse reactions (≥ 2%) reported with belatacept in both regimens (more 
intensive [MI] and less intensive [LI]) cumulative up to Year 3 were urinary tract infection, CMV 
infection, pyrexia, increased blood creatinine, pyelonephritis, diarrhoea, gastroenteritis, graft 
dysfunction, leukopenia, pneumonia, basal cell carcinoma, anaemia, dehydration. 
 
The most commonly reported adverse reactions (≥ 20%) among patients treated with both belatacept-
based regimens (MI and LI) up to Year 3 are diarrhoea, anaemia, urinary tract infection, peripheral 
oedema, constipation, hypertension, pyrexia, nausea, graft dysfunction, cough, vomiting, leukopenia, 
hypophosphataemia, and headache. 
 
Adverse reactions resulting in interruption or discontinuation of belatacept in ≥ 1% of patients up to 
Year 3 were renal vein thrombosis and CMV infection. 
 
Tabulated list of adverse reactions 
Presented in Table 2, by system organ classification and frequency categories, is the list of adverse 
reactions with at least a suspected causal relationship, reported in clinical trials cumulatively up to 
Year 3 and pooled for both belatacept regimens (MI and LI). 
 
The frequency categories are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); 
uncommon (≥ 1/1,000 to < 1/100). Within each frequency category adverse reactions are presented in 
order of decreasing seriousness. 
 



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Table 2:  Adverse reactions in clinical trials 
 
Infections and infestations  
Very Common urinary tract infection, upper respiratory infection, cytomegalovirus infection*, 

bronchitis 
Common sepsis, pneumonia, influenza, gastroenteritis, herpes zoster, sinusitis, herpes 

simplex, oral candidiasis, pyelonephritis, onychomycosis, BK virus infection, 
respiratory tract infection, candidiasis, rhinitis, cellulitis, wound infection, 
localised infection, herpes virus infection, fungal infection, fungal skin infection 

Uncommon progressive multifocal leukoencephalopathy*, cerebral fungal infection, 
cytomegalovirus (CMV) colitis, polyomavirus-associated nephropathy, genital 
herpes, staphylococcal infection, endocarditis, tuberculosis*, bronchiectasis, 
osteomyelitis, strongyloidiasis, blastocystis infection, giardiasis, lymphangitis 

 
Neoplasms, benign, malignant and unspecified (incl cysts and polyps)* 
Common squamous cell carcinoma of skin, basal cell carcinoma, skin papilloma 
Uncommon  EBV associated lymphoproliferative disorder**,lung cancer, rectal cancer, 

breast cancer, sarcoma, kaposi's sarcoma, prostate cancer, cervix carcinoma, 
laryngeal cancer, lymphoma, multiple myeloma, transitional cell carcinoma  

 
Blood and lymphatic system disorders
Very Common anaemia, leukopenia 
Common thrombocytopenia, neutropenia, leukocytosis, polycythaemia, lymphopenia 
Uncommon monocytopenia, pure red cell aplasia, agranulocytosis, haemolysis, 

hypercoagulation 
 
Immune system disorders 
Common 
 
 

blood immunoglobulin G decreased, blood immunoglobulin M decreased, 
 
 

Uncommon hypogammaglobulinaemia, seasonal allergy 
 
Endocrine disorders 
Common cushingoid  
Uncommon adrenal insufficiency
 
Metabolism and nutrition disorders 
Very Common hypophosphataemia, hypokalaemia, dyslipidaemia, hyperkalaemia, 

hyperglycaemia, hypocalcaemia 
Common weight increase, diabetes mellitus, dehydration, weight decrease, acidosis, fluid 

retention, hypercalcaemia, hypoproteinaemia 
Uncommon diabetic ketoacidosis, diabetic foot, alkalosis, decreased appetite, vitamin D 

deficiency 
 
Psychiatric disorders 
Very Common insomnia, anxiety
Common depression 
Uncommon abnormal dreams, mood swings, attention deficit/hyperactivity disorder, libido 

increased 
 
Nervous system disorders 
Very Common headache 
Common tremor, paraesthesia, cerebrovascular accident, dizziness, syncope, lethargy, 

neuropathy peripheral 
Uncommon encephalitis, Guillain-Barré syndrome*, brain oedema, intracranial pressure 

increased, encephalopathy, convulsion, hemiparesis, demyelination, facial palsy, 



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dysgeusia, cognitive disorder, memory impairment, migraine, burning sensation, 
diabetic neuropathy, restless leg syndrome 

 
Eye disorders 
Common cataract, ocular hyperaemia, vision blurred
Uncommon retinitis, conjunctivitis, eye inflammation, keratitis, photophobia, eyelid oedema
 
Ear and labyrinth disorders 
Common vertigo, ear pain, tinnitus 
Uncommon hypoacusis 
 
Cardiac disorders 
Common tachycardia, bradycardia, atrial fibrillation, cardiac failure, angina pectoris, left 

ventricular hypertrophy 
Uncommon acute coronary syndrome, atrioventricular block second degree, aortic valve 

disease, arrhythmia supraventricular 
 
Vascular disorders 
Very Common hypertension, hypotension
Common shock, infarction, haematoma, lymphocele, angiopathy, arterial fibrosis 
Uncommon venous thrombosis, arterial thrombosis, thrombophlebitis, arterial stenosis, 

intermittent claudication, flushing 
 
Respiratory, thoracic and mediastinal disorders
Very Common dyspnoea, cough
Common pulmonary oedema, wheezing, hypocapnea, orthopnoea, epistaxis, 

oropharyngeal pain 
Uncommon acute respiratory distress syndrome, pulmonary hypertension, pneumonitis, 

haemoptysis, bronchopneumopathy, painful respiration, pleural effusion, sleep 
apnoea syndrome, dysphonia, oropharyngeal blistering 

 
Gastrointestinal disorders 
Very Common diarrhoea, constipation, nausea, vomiting, abdominal pain 
Common dyspepsia, aphthous stomatitis, abdominal hernia 
Uncommon gastrointestinal disorder, pancreatitis, large intestinal ulcer, melaena, 

gastroduodenal ulcer, rectal haemorrhage, small intestinal obstruction, cheilitis, 
gingival hyperplasia, salivary gland pain, faeces discoloured 

 
Hepatobiliary disorders 
Common cytolytic hepatitis, liver function test abnormal 
Uncommon cholelithiasis, hepatic cyst, hepatic steatosis
 
Skin and subcutaneous tissue disorders 
Common acne, pruritis, alopecia, skin lesion, rash, night sweats, hyperhidrosis 
Uncommon psoriasis, hair growth abnormal, onychoclasis, penile ulceration, swelling face, 

trichorrhexis 
 
Musculoskeletal and connective tissue disorders 
Very Common arthralgia, back pain, pain in extremity
Common myalgia, muscular weakness, bone pain, joint swelling, intervertebral disc 

disorder, joint lock, muscle spasms, osteoarthritis 
Uncommon bone metabolism disorder, osteitis, osteolysis, synovitis 
 
Renal and urinary disorders 
Very Common proteinuria, blood creatinine increased, dysuria, haematuria



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Common renal tubular necrosis, renal vein thrombosis*, renal artery stenosis, glycosuria, 
hydronephrosis, vesicoureteric reflux, urinary incontinence, urinary retention, 
nocturia 

Uncommon renal artery thrombosis*, nephritis, nephrosclerosis, renal tubular atrophy, 
cystitis haemorrhagic, kidney fibrosis 

 
Reproductive system and breast disorders
Uncommon epididymitis, priapism, cervical dysplasia, breast mass, testicular pain, vulval 

ulceration, atrophic vulvovaginitis, infertility, scrotal oedema 
 
Congenital, familial and genetic disorders
Common hydrocele 
Uncommon hypophosphatasia 
 
General disorders and administration site conditions 
Very Common oedema peripheral, pyrexia 
Common chest pain, fatigue, malaise, impaired healing
Uncommon infusion related reaction*, irritability, fibrosis, inflammation, disease recurrence, 

feeling hot, ulcer 
 
Investigations 
Common c-reactive protein increased, blood parathyroid hormone increased 
Uncommon pancreatic enzymes increased, troponin increased, electrolyte imbalance, 

prostate-specific antigen increased, blood uric acid increased, urine output 
decreased, blood glucose decreased, CD4 lymphocytes decreased 

 
Injury, poisoning and procedural complications 
Very Common graft dysfunction 
Common chronic allograft nephropathy (CAN), incisional hernia 
Uncommon transplant failure, transfusion reaction, wound dehiscence, fracture, tendon 

rupture, procedural hypotension, procedural hypertension, post-procedural 
haematoma, procedural pain, procedural headache, contusion 

* See section “Description of selected adverse reactions”. 
** Includes all events reported over a median of 3.3 years in the Phase 3 studies, and a median of approximately 7 years in the Phase 2 study. 
 
Long-term extension in Study 1 and Study 2 
Of the 1209 randomized and transplanted patients in the two Phase 3 studies (see section 5.1), 
761 patients continued after Year 3 in a long-term extension period for up to an additional 4 years and 
continued to receive the study drug according to their original treatment assignment. As compared to 
the results from the initial 3 years, no new adverse reactions or increasing incidence of adverse 
reactions (listed above from the initial 3-year period) were detected during the 4-year long-term open 
label extension. 
 
Description of selected adverse reactions 
 
Malignancies and post-transplant lymphoproliferative disease  
Year 1 and 3 frequencies of malignancies are shown in Table 3, except for cases of PTLD which are 
presented at 1 year and > 3 years (median days of follow-up were 1,199 days for belatacept MI, 
1,206 days for belatacept LI, and 1,139 days for ciclosporin). The Year 3 frequency of malignant 
neoplasms, excluding non-melanoma skin cancers, was similar in the belatacept LI and ciclosporin 
groups and higher in the belatacept MI group. PTLD occurred at a higher rate in both belatacept 
treatment groups versus ciclosporin (see section 4.4). Non-melanoma skin cancers occurred less 
frequently with the belatacept LI regimen than with the ciclosporin or belatacept MI regimens. 
 



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Table 3: Malignancies occurring by treatment group (%) 
 Up to Year 1 Up to Year 3*,** 

Belatacept 
MI 

N= 477 
 

Belatacept 
LI 

N= 472 

Ciclosporin
N= 476 

 

Belatacept 
MI 

N= 477 

Belatacept 
LI 

N= 472 
 

Ciclosporin
N= 476 

 

Any malignant 
neoplasm 

3.4 1.9 3.4 8.6 5.7 7.1 

Non-melanoma 
skin cancer 

1.0 0.2 1.5 4.2 1.5 3.6 

Malignant 
neoplasms 
excluding non-
melanoma skin 
cancers 

2.3 1.7 1.9 4.4 4.2 3.6 

PTLD 0.8 0.8 0.2 1.7 1.3 0.6 
Malignancies 
excluding non-
melanoma skin 
cancer and PTLD 

1.5 0.8 1.7 2.7 3.2 3.4 

*Median follow-up excluding PTLD for pooled studies is 1,092 days for each treatment group. 
**Median follow-up for PTLD for pooled studies is 1,199 days for MI, 1,206 days for LI, and 1,139 days for ciclosporin. 
 
In the 3 studies (one Phase 2 and two Phase 3 studies, Study 1 and Study 2), the cumulative frequency 
of PTLD was higher in belatacept treated patients at the recommended dosing regimen (LI) (1.3%; 
6/472) than in the ciclosporin group (0.6%; 3/476), and was highest in the belatacept MI group (1.7%; 
8/477). Nine of 14 cases of PTLD in belatacept-treated patients were located in the CNS; within the 
observation period, 8 of 14 cases were fatal (6 of the fatal cases involved the CNS). Of the 
6 PTLD cases in the LI regimen, 3 involved the CNS and were fatal. 
 
EBV seronegative patients receiving immunosuppressants are at a particularly increased risk for PTLD 
(see sections 4.3 and 4.4). In clinical studies, belatacept-treated transplant recipients with EBV 
seronegative status were at an increased risk for PTLD compared with those who were EBV positive 
(7.7%; 7/91 versus 0.7%; 6/810, respectively). At the recommended dosing regimen of belatacept 
there were 404 EBV positive recipients and 4 cases of PTLD occurred (1.0%); 2 of these presented in 
the CNS. 
 
During the long-term extension period, malignancies (including PTLD) were reported in 10.3%, 8.4%, 
and 14.7% of patients in the belatacept MI, belatacept LI, and ciclosporin groups, respectively, in 
Study 1; and in 19.2%, 13.3% and 16.1% of patients in the belatacept MI, belatacept LI, and 
ciclosporin groups, respectively, in Study 2. Cases of PTLD varied by serostatus. In Study 1, one 
additional case of PTLD was reported in the ciclosporin group, in a patient who was EBV seropositive 
at the time of transplant. In Study 2, among patients who were EBV seropositive at the time of 
transplant, there was one case of PTLD in each of the three treatment groups. Among Study 2 patients 
who were EBV seronegative at the time of transplant (for whom use of belatacept is not 
recommended), there were three cases of PTLD in the belatacept LI group, and none in the belatacept 
MI and ciclosporin groups. 
 
Infections 
Year 1 and Year 3 frequencies of infections occurring by treatment group are shown in Table 4. The 
overall occurrence of tuberculosis infections and non-serious herpes infections were higher for 
belatacept regimens than for the ciclosporin regimen. The majority of cases of tuberculosis occurred in 
patients who currently live or previously lived in countries with a high prevalence of tuberculosis (see 
section 4.4). Overall occurrences of polyoma virus infections and fungal infections were numerically 
lower in the belatacept LI group compared with the belatacept MI and ciclosporin groups. 
 



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Within the belatacept clinical program, there were 2 patients diagnosed with PML. One fatal case of 
PML was reported in a renal transplant recipient treated with belatacept MI regimen, an IL-2 receptor 
antagonist, MMF, and corticosteroids for 2 years in a Phase 3 trial. The other case of PML was 
reported in a liver transplant recipient in a Phase 2 trial who received 6 months of treatment with an 
augmented belatacept MI regimen, MMF at doses higher than the recommended dose and 
corticosteroids (see section 4.4). 
 
Infections involving the CNS were more frequent in the belatacept MI group (8 cases, including the 
PML case discussed above; 1.7%) than the belatacept LI (2 cases, 0.4%) and ciclosporin (one case; 
0.2%) groups. The most common CNS infection was cryptococcal meningitis. 
 
Table 4:  Infections occurring by treatment group (%) 
 Up to Year 1 Up to Year 3* 

Belatacept 
MI 

N= 477 
 

Belatacept 
LI  

N= 472 
 

Ciclosporin 
N= 476 

 

Belatacept 
MI  

N= 477 
 

Belatacept 
LI  

N= 472 
 

Ciclosporin 
N= 476 

 

Infections and 
infestations  

70.7 71.8 73.7 79.2 82.0 80.6 

Serious infections  26.8 23.3 27.3 35.8 33.5 37.8 
Viral infections  26.4 25.0 27.7 38.8 39.0 36.1 
 CMV  11.1 11.9 13.7 13.8 13.8 14.7
 Polyomavirus 4.8 2.3 4.8 6.3 3.8 5.7
 Herpes  8.0 6.6 6.1 15.5 14.2 10.7
Fungal infections  13.8 11.0 15.1 22.9 16.7 20.6 
Tuberculosis  0.4 0.4 0.2 1.3 1.3 0.2 
*Median exposure for pooled studies is 1,092 days for each treatment group. 
 
During the long-term extension period, serious infections occurred in 30.3% and 23.5% of patients in 
the belatacept MI and LI groups, respectively, and in 27.2% of patients in the ciclosporin group in 
Study 1; and in 35.6% and 38.1% of patients in the belatacept MI and LI groups, respectively, and in 
37.9% of patients in the ciclosporin group in Study 2. There was one case of PML reported (Study 1) 
in the ciclosporin group at 82 months post-transplant (more than 56 days after discontinuing therapy). 
 
Graft thrombosis 
In a Phase 3 study in recipients of extended criteria donor (ECD) kidneys (Study 2), graft thrombosis 
occurred more frequently in the belatacept groups (4.3% and 5.1% for the MI and LI regimens 
respectively), versus 2.2% for ciclosporin. In another Phase 3 study in recipients of living donor and 
standard criteria deceased donor kidneys (Study 1), the incidence of graft thrombosis was 2.3% and 
0.4% for the MI and LI regimens respectively, versus 1.8% for ciclosporin. In a Phase 2 study, there 
were 2 cases of graft thrombosis, 1 each in MI and LI (incidence of 1.4% for both) versus 0 in the 
ciclosporin group. In general, these events occurred early and the majority resulted in graft loss. In 
postmarketing experience in patients with other predisposing risk factors for thrombosis of the renal 
allograft, renal allograft thrombosis has been reported when the initial dose of anti-thymocyte globulin 
was coadministered at the same or nearly the same time with the first dose of belatacept. (see section 
4.4). 
 
Infusion-related reactions 
Anaphylaxis has been reported post marketing(see section 4.4). 
 
Acute infusion-related reactions (reactions occurring within one hour of infusion) occurred in 5.5% of 
patients in the belatacept MI group and 4.4% of patients in the belatacept LI group up to Year 3. The 
most frequently reported acute infusion-related reactions in combined belatacept regimens were 
hypotension, hypertension, flushing and headache. Most events were not serious, were mild to 
moderate in intensity, and did not recur. When belatacept was compared to placebo infusions, there 



13 

were no differences in event rates (placebo infusions were administered at Weeks 6 and 10 of the 
belatacept LI regimen to blind the MI and LI regimens). 
 
Immunogenicity  
Antibodies directed against the belatacept molecule were assessed in 796 kidney transplant recipients 
(551 of these treated for at least 3 years) in the two Phase 3 studies. An additional 51 patients were 
treated for an average of 7 years in the long-term extension of a Phase 2 study. Anti-belatacept 
antibody development was not associated with altered clearance of belatacept. 
 
A total of 45 of 847 patients (5.3%) developed antibodies during treatment with belatacept. In the 
individual studies, the percentage of patients with antibodies ranged from 4.5% and 5.2% in the 
Phase 3 studies to 11.8% in the long-term extension of the Phase 2 study. However, immunogenicity 
rate normalised for duration of exposure was consistent at 2.0 to 2.1 per 100 patient years among the 
three studies. In 153 patients assessed for antibodies at least 56 days (approximately 7 half-lives) after 
discontinuation of belatacept, an additional 10 (6.5%) developed antibodies. In general, antibody titers 
were low, not usually persistent, and often became undetectable with continued treatment. 
 
To assess for the presence of neutralising antibodies, samples from 29 patients with confirmed binding 
activity to the modified cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) region of the 
molecule were assessed by an in vitro assay; 8 (27.6%) patients were shown to possess neutralising 
antibodies. The clinical relevance of such antibodies is unclear.  
 
Autoimmunity 
The occurrence of autoimmune events across the core clinical studies was infrequent, occurring at 
rates of 1.7%, 1.7%, and 1.9% by Year 3 for the MI, LI, and ciclosporin groups respectively. One 
patient on belatacept MI regimen developed Guillian-Barré syndrome which led to treatment 
discontinuation and subsequently resolved. Overall, the few reports across clinical studies suggest that 
prolonged exposure to belatacept does not predispose patients to an increased risk of development of 
autoimmune events. 
 
During the long-term extension period, autoimmune events occurred in 2.6% and 3.0% of patients in 
the belatacept MI and LI groups, respectively, and in 3.7% of patients in the ciclosporin group in 
Study 1; and in 5.8% and 3.5% of patients in the belatacept MI and LI groups, respectively, and in 0% 
of patients in ciclosporin group in Study 2. 
 
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. 
 
4.9 Overdose 
 
Single doses up to 20 mg/kg have been administered without apparent toxic effect. In case of 
overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse 
reactions and appropriate symptomatic treatment instituted. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Immunosuppressants, selective immunosuppressants, ATC code: 
L04AA28. 
 
Belatacept, a selective costimulation blocker, is a soluble fusion protein consisting of a modified 
extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) fused to a 



14 

portion (hinge-CH2-CH3 domains) of the Fc domain of a human immunoglobulin G1 antibody. 
Belatacept is produced by recombinant DNA technology in a mammalian cell expression system. Two 
amino acid substitutions (L104 to E; A29 to Y) were made in the ligand binding region of CTLA-4. 
 
Mechanism of action 
Belatacept binds to CD80 and CD86 on antigen presenting cells. As a result, belatacept blocks CD28 
mediated co-stimulation of T cells inhibiting their activation. Activated T cells are the predominant 
mediators of immunologic response to the transplanted kidney. Belatacept, a modified form of 
CTLA4-Ig, binds CD80 and CD86 more avidly than the parent CTLA4-Ig molecule from which it is 
derived. This increased avidity provides a level of immunosuppression that is necessary for preventing 
immune-mediated allograft failure and dysfunction.  
 
Pharmacodynamic effects 
In a clinical study, approximately 90% saturation of CD86 receptors on the surface of antigen-
presenting cells in the peripheral blood was observed following the initial administration of belatacept. 
During the first month post-transplantation, 85% saturation of CD86 was maintained. Up to month 3 
post-transplantation with the recommended dosing regimen, the level of CD86 saturation was 
maintained at approximately 70% and at month 12, approximately 65%. 
  
Clinical efficacy and safety  
Study 1 and 2: Phase 3 studies in renal transplant recipients 
The safety and efficacy of belatacept as part of an immunosuppressive regimen following renal 
transplantation were assessed in two randomised, partially-blinded, multicenter, 3 year studies with the 
primary endpoint specified at Year 1. These studies compared two dose regimens of belatacept (MI 
and LI) with ciclosporin in recipients of standard criteria (Study 1) or extended criteria (Study 2) 
donor organs. All patients received basiliximab, MMF, and corticosteroids. The more intensive (MI) 
regimen, which included higher and more frequent dosing during the first 6 months post transplant, 
resulted in 2-fold higher exposure to belatacept than the less intensive (LI) regimen during Months 2 
through 7 post transplant. Efficacy was similar between MI and LI while the overall safety profile was 
better for the LI. Therefore, the recommended dose of belatacept is the LI dosage regimen. 
 
Study 1: Recipients of Living Donor and Standard Criteria Deceased Donor Kidneys 
Standard criteria donor organs were defined as organs from a living donor, or a deceased donor with 
anticipated cold ischemia time of < 24 hours and not meeting the definition of extended criteria donor 
organs. Study 1 excluded (1) recipients undergoing a first transplant whose current PRA were ≥50%; 
(2) recipients undergoing a retransplantation whose current PRA were ≥30%; (3) recipients when 
previous graft loss was due to acute rejection and in case of a positive T-cell lymphocytotoxic cross 
match. 
 
In this study, 666 patients were enrolled, randomised, and transplanted; 219 to belatacept MI, 226 to 
belatacept LI, and 221 to ciclosporin. The median age was 45 years; 58% of donor organs were from 
living patients;  3% were re-transplanted; 69% of the study population was male; 61% of patients were 
white, 8% were black/African-American, 31% were categorised as of other races; 16% had PRA ≥ 
10%; and 41% had 4 to 6 HLA mismatches.  
 
The dose of corticosteroids used in all treatment groups was tapered during the first 6 months 
following transplantation. The median corticosteroid doses administered with the belatacept 
recommended regimen up to months 1, 3, and 6 were 20 mg, 12 mg and 10 mg, respectively. 
 
Study  2: Recipients of Extended Criteria Donor Kidneys 
Extended criteria donors were defined as deceased donors with at least one of the following: (1) donor 
age ≥ 60 years; (2) donor age ≥ 50 years and other donor comorbidities (≥ 2 of the following: stroke, 
hypertension, serum creatinine > 1.5 mg/dl); (3) donation after cardiac death or (4) anticipated cold 
ischemia time of ≥ 24 hours. Study 2 excluded recipients with a current PRA ≥ 30%, re-transplanted 
patients, and in case of a positive T-cell lymphocytotoxic cross match. 
 



15 

In this study, 543 patients were enrolled, randomised, and transplanted; 184 to belatacept MI, 175 to 
belatacept LI, and 184 to ciclosporin. The median age was 58 years; 67% of the study population was 
male; 75% of patients were white, 13% were black/African-American, 12% were categorised as of 
other races; 3% had PRA ≥ 10%; and 53% had 4 to 6 HLA mismatches.  
 
The dose of corticosteroids used in all treatment groups was tapered during the first 6 months 
following transplantation. The median corticosteroid doses administered with the belatacept 
recommended regimen up to months 1, 3, and 6 were 21 mg, 13 mg and 10 mg, respectively. 
 
Table 5 summarises results for belatacept LI compared with ciclosporin for the co-primary efficacy 
endpoints of death and graft loss, composite renal impairment, and acute rejection (defined as 
clinically suspected biopsy proven acute rejection). Patient and graft survival were similar between 
belatacept and ciclosporin. Fewer patients met the composite renal impairment endpoint and mean 
GFR was higher with belatacept compared to ciclosporin.  
 
Acute rejection (AR) occurred more frequently with belatacept versus ciclosporin in Study 1 and with 
similar frequency with belatacept versus ciclosporin in Study 2. Approximately 80% of AR episodes 
occurred by Month 3 and were infrequent after Month 6. In Study 1, 11/39 belatacept and 
3/21 ciclosporin acute rejections were Banff 97 grade ≥ IIb by Year 3. In Study 2, 9/33 belatacept and 
5/29 ciclosporin acute rejections were Banff 97 grade ≥ IIb by Year 3. AR was treated more often with 
lymphocyte depleting therapy (a risk factor for PTLD; see section 4.4) in the belatacept group than the 
ciclosporin group. In both studies, in patients with AR by Year 2, donor-specific antibodies, one of the 
criteria for diagnosis of antibody-mediated rejection, were present in 6% (2/32, Study 2)-8% (3/39, 
Study 1) and 20% (4/20, Study 1)-26% (7/27, Study 2) in the belatacept and ciclosporin groups by 
year 3, respectively. By Year 3 recurrent AR was similar across groups (< 3%) and subclinical AR 
identified on the 1 year protocol biopsy was 5% in both groups. In Study 1, 5/39 belatacept patients 
versus 1/21 ciclosporin patients with AR had experienced graft loss, and 5/39 belatacept patients and 
no ciclosporin patients with AR had died by Year 3. In Study 2, 5/33 belatacept patients versus 
6/29 ciclosporin patients with AR had experienced graft loss, and 5/33 belatacept patients versus 
5/29 ciclosporin patients with AR had died by Year 3. In both studies, mean GFR following AR was 
similar in belatacept and ciclosporin treated patients. 
 



16 

Table 5:  Key efficacy outcomes at years 1 and 3 
 Study 1: living and 

standard criteria deceased 
donors 

Study 2: extended criteria 
donors 

Parameter Belatacept 
LI

Ciclosporin Belatacept 
LI

Ciclosporin 

 N = 226 N = 221 N = 175 N = 184 

Patient and Graft Survival (%)  
 Year 1 
 [95% CI] 
  

 
96.5 

[94.1-98.9] 

 
93.2 

[89.9-96.5] 

 
88.6 

[83.9-93.3] 

 
85.3 

[80.2-90.4] 

 Year 3 
 [95% CI] 

92.0 
[88.5-95.6] 

88.7 
[84.5-92.9] 

82.3 
[76.6-87.9] 

79.9 
[74.1-85.7] 

Death (%) 
  Year 1 

 
1.8 

 
3.2 

 
2.9 

 
4.3 

 Year 3 4.4 6.8 8.6 9.2 
Graft Loss (%) 
 Year 1 

 
2.2 

 
3.6 

 
9.1 

 
10.9 

 Year 3 4.0 4.5 12.0 12.5 
% of Patients meeting Composite 
renal impairment endpoint at 
Year 1a 

 
54.2 

 

 
77.9 

 
76.6 

 

 
84.8 

 
 P-value < 0.0001 - < 0.07 - 
AR (%) 
 Year 1 (%) 
 [95% CI] 

 
17.3 

[12.3-22.2] 

 
7.2 

[3.8-10.7] 

 
17.7 

[12.1-23.4] 

 
14.1 

[9.1-19.2] 
 Year 3 (%) 
 [95% CI] 

17.3 
[12.3-22.2] 

9.5 
[5.6-13.4] 

18.9 
[13.1-24.7] 

15.8 
[10.5-21.0] 

Mean Measured 
GFRb  ml/min/1.73 m2 
 Year 1 

 
 

63.4 

 
 

50.4 

 
 

49.6 

 
 

45.2 
 Year 2 67.9 50.5 49.7 45.0
Mean Calculated GFRc 
ml/min/1.73 m2 

 Month 1  
 Year 1 

 
 

61.5 
65.4 

 
 

48.1 
50.1 

 
 

39.6 
44.5 

 
 

31.8 
36.5 

 Year 2 65.4 47.9 42.8 34.9
 Year 3 65.8 44.4 42.2 31.5 

aProportion of Patients with Measured GFR < 60 ml/min/1.73 m2 or with a Decrease in Measured GFR ≥ 10 ml/min/1.73 m2 from Month 3 to 
Month 12. 
b Measured GFR was assessed by iothalamate at Year 1 and 2 only 
c Calculated GFR was assessed by MDRD formula at Month 1, Years 1, 2, and 3 
 
Progression of Chronic Kidney Disease (CKD) Staging 
In Study 1 by Year 3, mean calculated GFR was 21 ml/min/1.73 m2 higher with belatacept, and 10% 
and 20% of patients reached CKD stage 4/5 (GFR < 30 ml/min/1.73 m2) with belatacept versus 
ciclosporin, respectively. In Study 2 by Year 3, mean calculated GFR was 11 ml/min/1.73 m2 higher 
with belatacept, and 27% and 44% of patients reached CKD stage 4/5 (GFR < 30 ml/min/1.73 m2) 
with belatacept versus ciclosporin, respectively. 
 
Chronic Allograft Nephropathy/Interstitial Fibrosis and Tubular Atrophy (IFTA) 
The prevalence of CAN/IFTA at Year 1 in Studies 1 and 2, was numerically lower with belatacept 
than ciclosporin (~ 9.4% and 5%, respectively). 
 



17 

New Onset Diabetes Mellitus and Blood Pressure 
In a prespecified pooled analysis of Studies 1 and 2 at Year 1, the incidence of new onset diabetes 
mellitus (NODM), defined as use of an antidiabetic agent for ≥ 30 days or ≥ 2 fasting plasma glucose 
values > 126 mg/dl (7.0 mmol/l) post-transplantation, was 5% with belatacept and 10% with 
ciclosporin. At Year 3, the incidence of NODM was 8% with belatacept and 10% with ciclosporin. 
 
For Studies 1 and 2 at Years 1 and 3, belatacept was associated with 6 to 9 mmHg lower mean systolic 
blood pressure, approximately 2 to 4 mmHg lower mean diastolic blood pressure, and less use of 
antihypertensive medicinal products than ciclosporin.  
 
Long-term extension in Study 1 and Study 2 
A total of 321 belatacept (MI: 155 and LI: 166) and 136 ciclosporin patients completed 3 years of 
treatment in Study 1 and entered the 4-year long-term open label extension period (up to 7 years in 
total). More patients discontinued in the ciclosporin group (32.4%) versus each belatacept group 
(17.4% and 18.1% in MI and LI groups, respectively) during the long-term extension period. A total of 
217 belatacept (MI: 104 and LI: 113) and 87 ciclosporin patients completed 3 years of treatment in 
Study 2 and entered the 4-year long-term open label extension period (up to 7 years in total). More 
patients discontinued in the ciclosporin group (34.5%) versus each belatacept group (28.8% and 25.7% 
for MI and LI groups, respectively) during the long-term extension period. 
 
As compared to ciclosporin and assessed by the hazard ratio (HR) estimates (for death or graft loss) 
from an ad hoc Cox regression analysis, overall patient and graft survival was higher for belatacept-
treated patients in Study 1, HR 0.588 (95% CI: 0.356-0.972) for the MI group and HR 0.585 (95% CI: 
0.356-0.961) for the LI group, and comparable across treatment groups in Study 2, HR 0.932 (95% CI: 
0.635-1.367) for the MI group and HR 0.944 (95% CI: 0.644-1.383) for the LI group. The overall 
proportion of patients with death or graft loss was lower in belatacept-treated patients (MI: 11.4%, LI: 
11.9%) as compared to ciclosporin-treated patients (17.6%) in Study 1. The overall proportion of 
patients with death or graft loss was comparable across treatment groups (29.3%, 30.9%, and 28.3% 
for MI, LI and ciclosporin, respectively) in Study 2. In Study 1, in the MI, LI, and ciclosporin groups, 
respectively, death occurred in 7.8%, 7.5%, and 11.3% of patients, and graft loss occurred in 4.6%, 
4.9%, and 7.7% of patients. In Study 2, in the MI, LI, and ciclosporin groups, respectively, death 
occurred in 20.1%, 21.1%, and 15.8% of patients, and graft loss occurred in 11.4%, 13.1%, and 15.8% 
of patients. The higher proportion of deaths in the LI group in Study 2 was mainly due to neoplasms 
(MI: 3.8%, LI: 7.1%, ciclosporin: 2.3%). 
 
The higher calculated GFR observed in belatacept-treated patients relative to ciclosporin-treated 
patients during the first 3 years was maintained over the long-term extension period. In Study 1, mean 
calculated GFR at 7 years was 74.0, 77.9 and 50.7 mL/min/1.73 m2 in the belatacept MI, belatacept LI 
and ciclosporin groups, respectively. In Study 2, mean calculated GFR at 7 years was 57.6, 59.1 and 
44.6 mL/min/1.73 m2, in the same groups, respectively. The time to death, graft loss, or GFR <30 
mL/min/1.73 m2 was analyzed over the 7-year period: in Study 1, approximately 60% reduction in the 
risk of death, graft loss, or GFR <30 mL/min/1.73 m2 was observed among patients in the belatacept 
groups as compared with those assigned to ciclosporin. In Study 2, approximately 40% reduction in 
this risk was observed among patients in the belatacept groups as compared with those assigned to 
ciclosporin. 
 
Phase 2 liver transplant study 
A single, randomised, multi-center, controlled Phase 2 trial of belatacept in de novo orthotopic liver 
transplant recipients was conducted. A total of 250 subjects were randomised to 1 of 5 treatment 
groups (3 belatacept and 2 tacrolimus groups). The belatacept dosing used in this liver study was 
higher in all 3 belatacept arms than the belatacept dosing used in the Phase 2 and 3 renal transplant 
studies. 
 
An excess in mortality and graft loss was observed in the belatatacept LI + MMF group and an excess 
in mortality was observed in the belatacept MI + MMF group. No pattern was identified in the causes 
of death. There was an increase in viral and fungal infections in the belatacept groups versus the 



18 

tacrolimus groups, however overall frequency of serious infections was not different among all 
treatment groups (see section 4.4).  
 
Elderly 
Two hundred seventeen (217) patients 65 years and older received belatacept across one Phase 2 and 
two Phase 3 renal studies. 
Elderly patients demonstrated consistency with the overall study population for safety and efficacy as 
assessed by patient and graft survival, renal function, and acute rejection. 
 
Paediatric population 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
belatacept in one or more subsets of the paediatric population in renal transplantation (see section 4.2 
for information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Absorption 
The pharmacokinetics of belatacept in renal transplant patients and healthy subjects appeared to be 
comparable. The pharmacokinetics of belatacept was linear and the exposure to belatacept increased 
proportionally in healthy subjects after a single intravenous infusion dose of 1 to 20 mg/kg. The mean 
(range) pharmacokinetic parameters of belatacept after multiple intravenous infusions at doses of 5 
and 10 mg/kg in renal transplant subjects were: terminal half-life, 8.2 (3.1-11.9) and 9.8 (6.1-15.1) 
days, respectively; systemic clearance 0.51 (0.33-0.75) and 0.49 (0.23-0.70) ml/h/kg, respectively; and 
distribution volume at steady state, 0.12 (0.09-0.17) and 0.11 (0.067-0.17) l/kg, respectively. At the 
recommended dosing regimen, serum concentration generally reached steady-state by Week 8 in the 
initial phase following transplantation and by Month 6 during the maintenance phase. At Month 1, 4, 
and 6 post-transplant, the mean (range) trough concentrations of belatacept were 22.7 (11.1-45.2), 
7.6 (2.1-18.0), and 4.0 (1.5-6.6) μg/ml, respectively.  
 
Distribution 
Based on population pharmacokinetic analysis of 944 renal transplant patients up to 1 year post-
transplant, the pharmacokinetics of belatacept were similar at different time periods post-transplant. 
The trough concentration of belatacept was consistently maintained up to 5 years post-transplant. 
Minimal systemic accumulation of belatacept occurred upon multiple infusions of 5 or 10 mg/kg doses 
in renal transplant patients every 4 weeks. The accumulation index for belatacept at steady state is 1.1. 
 
Elimination 
Population pharmacokinetic analyses in renal transplant patients revealed that there was a trend toward 
higher clearance of belatacept with increasing body weight. No clinically relevant effects of age, 
gender, race, renal function (calculated GFR), diabetes, or concomitant dialysis on clearance of 
belatacept was identified. 
 
There is no data available in patients with hepatic impairment. 
 
5.3 Preclinical safety data 
 
Belatacept has less activity in rodents than abatacept, a fusion protein that differs from belatacept by 
two amino acids in the CD80/86 binding domains. Because of abatacept’s similarity to belatacept in 
structure and mechanism of action and its higher activity in rodents, abatacept was used as a more 
active homolog for belatacept in rodents. Therefore, preclinical studies conducted with abatacept have 
been used to support the safety of belatacept in addition to the studies conducted with belatacept. 
 
No mutagenicity or clastogenicity was observed with abatacept in a battery of in vitro studies. In a 
mouse carcinogenicity study, increases in the incidence of malignant lymphomas and mammary 
tumours (in females) occurred. The increased incidence of lymphomas and mammary tumours 
observed in mice treated with abatacept may have been associated with decreased control of murine 
leukaemia virus and mouse mammary tumour virus, respectively, in the presence of long-term 



19 

immunomodulation. In a six-month and one-year toxicity study in cynomolgus monkeys with 
belatacept and abatacept, respectively, no significant toxicity was observed. Reversible 
pharmacological effects consisted of minimal decreases in serum IgG and minimal to severe lymphoid 
depletion of germinal centers in the spleen and/or lymph nodes. No evidence of lymphomas or 
preneoplastic morphologic changes was observed in either study. This was despite the presence in the 
abatacept study of a virus, lymphocryptovirus, known to cause these lesions in immunosuppressed 
monkeys within the time frame of these studies. The viral status was not determined in the belatacept 
study but, as this virus is prevalent in monkeys, it was likely present in these monkeys as well.  
In rats, belatacept had no undesirable effects on male or female fertility. Belatacept was not 
teratogenic when administered to pregnant rats and rabbits at doses up to 200 mg/kg and 100 mg/kg 
daily, respectively, representing approximately 16 and 19 times the exposure associated with the 
maximum recommended human dose (MRHD) of 10 mg/kg based on AUC. Belatacept administered 
to female rats daily during gestation and throughout the lactation period was associated with infections 
in a small percentage of dams at all doses (≥ 20 mg/kg, ≥ 3 times the MRHD exposure based on 
AUC), and produced no adverse effects in offspring at doses up to 200 mg/kg representing 19 times 
the MRHD exposure based on AUC. Belatacept was shown to cross the placenta in rats and rabbits. 
Abatacept administered to female rats every three days during gestation and throughout the lactation 
period, produced no adverse effects in offspring at doses up to 45 mg/kg, representing 3 times the 
exposure associated with the MRHD of 10 mg/kg based on AUC. However, at 200 mg/kg, 11 times 
the MRHD exposure, alterations in immune function were observed consisting of a 9-fold increase 
in T-cell dependent antibody response in female pups and thyroid inflammation in one female pup. It 
is not known whether these findings indicate a risk for development of autoimmune diseases in 
humans exposed in utero to abatacept or belatacept. 
 
Studies in rats exposed to abatacept have shown immune system abnormalities including a low 
incidence of infections leading to death (juvenile rats) as well as inflammation of the thyroid and 
pancreas (both juvenile and adult rats). Studies in adult mice and monkeys have not demonstrated 
similar findings. It is likely that the increased susceptibility to opportunistic infections observed in 
juvenile rats is associated with the exposure to abatacept before development of memory responses. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sucrose 
Sodium dihydrogen phosphate monohydrate 
Sodium chloride 
Sodium hydroxide (for pH adjustment) 
Hydrochloric acid (for pH adjustment) 
 
6.2 Incompatibilities 
 
This medicinal product must not be mixed with other medicinal products except those mentioned in 
section 6.6.  
 
NULOJIX should not be used with siliconised syringes in order to avoid aggregate formation (see 
section 6.6). 
 
6.3 Shelf life 
 
Unopened vials 
3 years 
 
After reconstitution 
The reconstituted solution should be transferred from the vial to the infusion bag or bottle 
immediately. 



20 

 
After dilution 
Chemical and physical in-use stability of the solution for infusion has been demonstrated for 24 hours 
when stored in a refrigerator (2°C - 8°C). From a microbiological point of view, the product should be 
used immediately. If not used immediately, the solution for infusion may be stored in a refrigerator 
(2°C - 8°C) for up to 24 hours. Out of these 24 hours, the solution for infusion may be stored below 
25°C for a maximum of 4 hours. Do not freeze. 
The NULOJIX infusion must be completed within 24 hours of reconstitution of the powder. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2°C - 8°C). 
Store in the original package in order to protect from light. 
For storage conditions after reconstitution or dilution of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
NULOJIX is supplied in a type I flint glass vial with a stopper (grey butyl rubber) and flip off seal 
(aluminum). Each vial is co-packaged with a disposable polypropylene syringe. 
 
Pack sizes: 1 vial and 1 syringe or 2 vials and 2 syringes. 
 
Not all pack-sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
 Use aseptic technique to reconstitute the vials and dilute the solution for administration. 
 Use the silicone-free disposable syringe provided to make up the vials and to add the solution to 

the infusion. This will avoid aggregate formation (see section 6.2). 
 Do not shake the vials. This will avoid foam formation. 
 The solution for infusion is to be used in conjunction with a sterile, non-pyrogenic, low protein 

binding filter (pore size of 0.2 µm to 1.2 µm). 
 
Dose selection and reconstitution of the vials 
Calculate the dose and number of NULOJIX vials required. Each NULOJIX vial provides 250 mg of 
belatacept. 
 Total dose of belatacept in mg equals the patient weight in kg times the belatacept dose in mg/kg 

(5 or 10 mg/kg, see section 4.2).  
 Dose modification of NULOJIX is not recommended for a change in body weight of less than 

10%. 
 Number of vials required equals the belatacept dose in mg divided by 250 rounded up to the next 

full number of vials.  
 Make up each vial with 10.5 ml reconstitution solution.  
 Volume of the reconstituted solution required (ml) equals total belatacept dose in mg divided 

by 25. 
 
Practical details on the reconstitution of vials 
Using aseptic technique, make up each vial with 10.5 ml of one of the following solvents (sterile water 
for injections, sodium chloride 9 mg/ml (0.9%) solution for injection or 5% glucose solution for 
injection), using the co-packed disposable syringe (necessary to avoid aggregate formation) and an 18-
21 gauge needle. Syringes are marked in units of 0.5 ml; therefore, the calculated dose should be 
rounded to the nearest 0.5 ml. 
 
Remove the flip off seal from the vial and wipe the top with an alcohol swab. Insert the syringe needle 
into the vial through the centre of the rubber stopper. Direct the stream of fluid to the glass wall of the 
vial and not into the powder. Remove the syringe and needle after 10.5 ml of reconstitution fluid has 
been added to the vial.  



21 

 
To minimize foam formation, gently swirl and invert the vial for at least 30 seconds or until the 
powder is completely dissolved. Do not shake. Although some foam may remain on the surface of the 
reconstituted solution, a sufficient excess of belatacept is included in each vial to account for 
withdrawal losses. Thus, 10 ml of a 25 mg/ml belatacept solution can be withdrawn from each vial.  
 
The reconstituted solution should be clear to slightly opalescent and colourless to pale yellow. Do not 
use if opaque particles, discolouration or other foreign particles are present. It is recommended to 
tranfer the reconstituted solution from the vial to the infusion bag or bottle immediately. 
 
Practical details on the preparation of the solution for infusion 
After reconstitution, dilute the product to 100 ml with sodium chloride 9 mg/ml (0.9%) solution for 
injection or 5% glucose solution for injection. From a 100 ml infusion bag or bottle (typically, an 
infusion volume of 100 ml will be appropriate for most patients and doses, but total infusion volume 
ranging from 50 ml to 250 ml may be used), withdraw a volume of sodium chloride 9 mg/ml (0.9%) 
solution for injection or 5% glucose solution for injection equal to the volume (ml equals total dose 
in mg divided by 25) of the reconstituted belatacept solution required to provide the dose and discard 
it. Slowly add the required amount of reconstituted belatacept solution from each vial to the infusion 
bag or bottle using the same disposable syringe used for reconstitution of the powder. Gently mix the 
infusion container. The concentration of belatacept in the infusion should be between 2 mg and 10 mg 
belatacept per ml solution.  
 
Any unused portion in the vials must be discarded in accordance with local requirements. 
 
Administration 
When reconstitution and dilution are performed under aseptic conditions, the NULOJIX infusion 
should be started immediately or must be completed within 24 hours of reconstitution of the powder. 
If not used immediately, the solution for infusion may be stored in the refrigerator (2°C - 8°C) for up 
to 24 hours. Do not freeze. The solution for infusion may be stored for a maximum of 4 hours of the 
total 24 hours below 25°C. Infusion must be completed within 24 hours of reconstitution of the 
powder. Prior to administration, the solution for infusion should be inspected visually for particulate 
matter or discolouration. Discard the solution if any particulate matter or discolouration is observed. 
The entire, fully diluted infusion should be administered over a period of 30 minutes and must be 
administered with an infusion set and a sterile, non-pyrogenic, low protein binding filter (pore size of 
0.2 μm to 1.2 μm). Following administration, it is recommended that the intravenous line be flushed 
with infusion fluid to ensure administration of the complete dose. 
Do not store any unused portion of the solution for infusion for reuse. 
 
NULOJIX 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 coadministration of 
NULOJIX with other agents. 
 
Disposal 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Bristol-Myers Squibb Pharma EEIG 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 
 



22 

8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/11/694/001-002 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 17 June 2011 
Date of latest renewal: 18 February 2016 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this product is available on the website of the European Medicines Agency 
http://www.ema.europa.eu. 
 
  



23 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 
A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT 



24 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
 
Name and address of the manufacturer of the biological active substance 
 
Bristol-Myers Squibb Company 
6000 Thompson Road, East Syracuse 
New York 13057 – U.S.A. 
 
Name and address of the manufacturer responsible for batch release 
 
Swords Laboratories T/A Bristol-Myers Squibb Cruiserath Biologics 
Cruiserath Road, Mulhuddart 
Dublin 15, D15 H6EF 
Ireland 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product 
Characteristics, section 4.2). 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
 Periodic Safety Update Reports  
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT   
 
 Risk Management Plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP. 
 
An updated RMP should be submitted: 
 At the request of the European Medicines Agency; 
 Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of an 
important (pharmacovigilance or risk minimisation) milestone being reached. 

  



25 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 

  



26 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
 
 



27 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
NULOJIX 250 mg powder for concentrate for solution for infusion 
belatacept 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial contains 250 mg belatacept. 
After reconstitution, each ml of concentrate contains 25 mg belatacept. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sucrose, sodium dihydrogen phosphate monohydrate, sodium chloride, and for 
pH adjustment sodium hydroxide and hydrochloric acid. Read the package leaflet before use. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for concentrate for solution for infusion 
 
1 vial 
1 syringe 
 
2 vials 
2 syringes 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For single use only. 
Read the package leaflet before use. 
Intravenous use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Only use co-packed syringe for reconstitution and dilution. 
 
 
8. EXPIRY DATE 
 
EXP 



28 

See leaflet for shelf-life after reconstitution and dilution.  
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Store in the original package in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
Discard any unused solution. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bristol-Myers Squibb Pharma EEIG 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/11/694/001 
EU/1/11/694/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 



29 

 
PC: 
SN: 
<NN:> 



30 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING  
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
NULOJIX 250 mg powder for concentrate  
belatacept 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial contains 250 mg belatacept. 
After reconstitution, each ml of concentrate contains 25 mg belatacept. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sucrose, sodium dihydrogen phosphate monohydrate, sodium chloride, and for 
pH adjustment sodium hydroxide and hydrochloric acid. Read the package leaflet before use. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for concentrate 
250 mg 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For single use only. 
Read the package leaflet before use. 
Intravenous use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Only use co-packed syringe for reconstitution and dilution. 
 
 
8. EXPIRY DATE 
 
EXP 
Read the package leaflet before use. 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Store in the original package in order to protect from light. 



31 

 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
Discard any unused solution. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bristol-Myers Squibb Pharma EEIG 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/11/694/001 
EU/1/11/694/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
 
  



32 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 
 



33 

Package leaflet: Information for the user 
 

NULOJIX 250 mg powder for concentrate for solution for infusion 
belatacept 

 
 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
 Keep this leaflet. You may need to read it again. 
 If you have any further questions, ask your doctor or pharmacist. 
 If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet: 
1. What NULOJIX is and what it is used for 
2. What you need to know before you use NULOJIX 
3. How to use NULOJIX 
4. Possible side effects 
5. How to store NULOJIX 
6. Contents of the pack and other information 
 
 
1. What NULOJIX is and what it is used for 
 
NULOJIX contains the active substance belatacept which belongs to a group of medicines called 
immunosuppressants. These are medicines that reduce the activity of the immune system, the body's 
natural defences. 
 
NULOJIX is used in adults to prevent the immune system from attacking your transplanted kidney and 
causing transplant rejection. It is used with other immunosuppressive medicines, including 
mycophenolic acid and corticosteroids. It is also recommended to administer an interleukin(IL)-2 
receptor antagonist during the first week after transplantation. 
 
 
2. What you need to know before you use NULOJIX 
 
Do not use NULOJIX 
 If you are allergic to belatacept or any of the other ingredients of the medicine (listed in section 

6). Allergic reactions related to belatacept use have been reported in the clinical studies.  
 If you have not been exposed to the Epstein-Barr virus (EBV) or are uncertain of previous 

exposure, you must not be treated with NULOJIX. EBV is the virus that causes glandular fever. If 
you have not been exposed to it, you are at a higher risk of getting a type of cancer called post-
transplant lymphoproliferative disorder (PTLD). If you are not sure if you have been infected with 
the virus before, ask your doctor. 

 
Warnings and precautions 
Post-transplant lymphoproliferative disorder 
Treatment with NULOJIX increases the risk of getting a type of cancer called post-transplant 
lymphoproliferative disorder (PTLD). With NULOJIX treatment, this more often develops in the brain 
and can lead to death. People are at a higher risk of developing PTLD in the following cases: 
 If you have not been exposed to EBV prior to your transplant 
 If you are infected with a virus called cytomegalovirus (CMV) 
 If you have been given a therapy for treatment of acute rejection, such as antithymocyte globulin 

to reduce T-cells. T-cells are cells responsible for maintaining your body's ability to resist disease 
and infections. They may cause rejection of your transplanted kidney.  

 If you are not sure about any of these conditions, ask you doctor. 
 



34 

Serious infections 
Serious infections can happen with NULOJIX treatment and can lead to death. 
NULOJIX weakens the body’s ability to fight infections. Serious infections can include  
 Tuberculosis  
 Cytomegalovirus (CMV), a virus that can cause serious tissue and blood infections  
 Shingles 
 Other herpes virus infections. 
 
There have been reports of a rare type of brain infection called progressive multifocal 
leukoencephalopathy (PML) that have occurred in patients who have been given NULOJIX. PML 
often leads to severe disability or death.  
 
Tell your family or caregiver about your treatment. You might get symptoms that you might not be 
aware of yourself. Your doctor may need to investigate your symptoms to rule out PML, PTLD or 
other infections. For a list of symptoms please see section 4, “Possible side effects”.  
 
Skin cancer 
Limit your exposure to sunlight and ultraviolet (UV) light whilst using NULOJIX. Wear protective 
clothing and use a sunscreen with a high protection factor. People who use NULOJIX have a higher 
risk of getting certain other types of cancer, especially skin cancer. 
 
Blood clotting in your transplanted kidney 
Depending on the type of kidney transplant that you received, you may be at higher risk of blood 
clotting in your transplanted kidney. 
 
Use in liver transplants 
The use of NULOJIX is not recommended if you have had a liver transplant.  
 
Use with other immunosuppressive medicines 
Nulojix is normally given with steroids. Too rapid reduction of steroid intake can increase the risk that 
your body may reject the transplanted kidney. Please take the exact steroid dose as determined by your 
doctor. 
 
Children and adolescents 
NULOJIX has not been studied in children and adolescents under 18 years of age, therefore it is not 
recommended in this age group. 
 
Other medicines and NULOJIX 
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines. 
Ask your doctor or pharmacist for advice before taking any other medicine while using NULOJIX. 
 
The use of live vaccines should be avoided with the use of NULOJIX. Tell your doctor if you need to 
have vaccinations. Your doctor will advise you what to do.  
 
Pregnancy and breast-feeding 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor for advice before taking this medicine. 
If you become pregnant while using NULOJIX, tell your doctor.  
Do not use NULOJIX if you are pregnant unless your doctor specifically recommends it. The effects 
of NULOJIX in pregnant women are not known. You must not get pregnant while using NULOJIX. If 
you are of child bearing potential, you should use effective contraception during treatment with 
NULOJIX and up to 8 weeks after the last dose of treatment since the potential risk to 
embryonic/foetal development is unknown. Your doctor will advise you about using a reliable 
contraceptive.  
 
You must stop breast-feeding if you are being treated with NULOJIX. It is not known whether 
belatacept, the active substance, passes into human milk.  



35 

 
Driving and using machines 
Belatacept has a minor influence on the ability to drive and use machines. However you should not 
drive or operate any machines if you are feeling tired or unwell after receiving NULOJIX. 
 
Important information about some of the ingredients of NULOJIX 
Tell your doctor if you are on a low-sodium (low-salt) diet before you are treated with NULOJIX.  
This medicine contains 0.65 mmol (or 15 mg) sodium per vial which corresponds to 1.95 mmol (or 
45 mg) sodium per maximum dose of three vials. 
 
 
3. How to use NULOJIX 
 
Treatment with NULOJIX will be prescribed and supervised by a specialist in kidney transplantation. 
NULOJIX will be given to you by a healthcare professional.  
It will be given to you by infusion (as a "drip") into one of your veins over a period of about 
30 minutes.  
 
The recommended dose is based on your body weight (in kg) and will be calculated by a healthcare 
professional. The dose and treatment frequency is given below. 
 
Initial Phase Dose 
Day of transplantation, prior to implantation (Day 1)

10 mg/kg Day 5, Day 14 and Day 28 
End of Week 8 and Week 12 after transplantation
Maintenance Phase Dose 
Every 4 weeks (± 3 days) starting at end of week 16 after transplantation 5 mg/kg

 
Information for medical and healthcare professionals on dose calculation, preparation and 
administration of NULOJIX is provided at the end of the leaflet.  
 
If you are given more NULOJIX than you should  
If this happens, your doctor will monitor you for any signs or symptoms of side effects, and treat these 
symptoms if necessary.  
 
If you forget to use NULOJIX 
It is very important for you to keep all appointments to receive NULOJIX. If you miss receiving 
NULOJIX when you are supposed to, ask your doctor when to schedule your next dose.  
 
If you stop using NULOJIX 
Your body may reject the transplanted kidney if you stop using NULOJIX. The decision to stop using 
NULOJIX should be discussed with your doctor and another therapy will generally be started.  
If you stop treatment with NULOJIX for a long period of time, without taking any other medicines to 
prevent rejection, and then restart, it is not known if belatacept will have the same effect as before.  
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. However, 
NULOJIX can cause serious side effects that may need treatment. 
Tell your family or caregiver about your treatment as you might get symptoms that you might not be 
aware of yourself. 
 
Tell your doctor immediately if you or your family notice any symptoms listed below: 
 



36 

Nervous system symptoms may include memory lapse; speech and communication difficulties; a 
change in your mood or behaviour; confusion or inability to control your muscles; weakness on one 
side of the body; vision changes; or headache. 
 
Infection symptoms may include fever; unexplained weight loss; swollen glands; cold symptoms such 
as a runny nose or sore throat; cough with sputum; blood in your sputum; earache; cuts or scrapes that 
are red; warm and oozing pus. 
 
Kidney or bladder symptoms may include tenderness at the site of your transplanted kidney; difficulty 
passing urine; changes in the amount of urine you produce; blood in the urine; pain or burning on 
urination. 
 
Gastrointestinal symptoms may include pain on swallowing; painful mouth ulcers; white patches in 
the mouth or throat; upset stomach; stomach pain; vomiting; or diarrhoea. 
 
Skin changes may include unexpected bruising or bleeding; brown or black skin lesion with uneven 
borders, or one part of the lesion does not look like the other; a change in the size and colour of a 
mole; or a new skin lesion or bump. 
 
Allergic reactions may include, but are not limited to, rash; reddened skin; hives; itching; lip swelling; 
tongue swelling; swelling of the face; swelling over entire body; chest pain; shortness of breath; 
wheezing; or dizziness.. 
 
Very common side effects (may affect more than 1 in 10 people) are:  
 Bladder or kidney infection, upper respiratory infection, CMV infection (can cause serious blood 

and tissue infections), fever, cough, bronchitis 
 Shortness of breath 
 Constipation, diarrhoea, nausea, vomiting, abdominal pain  
 High blood pressure, low blood pressure  
 Headache, difficulty sleeping, feeling nervous or anxious, swelling of the hands and feet 
 Joint pain, back pain, pain in the extremities 
 Pain when passing urine, blood in the urine 
Tests may show: 
 Low blood count or anaemia, low white blood cell count 
 Increased amounts of creatinine in your blood (blood test used to measure kidney function), 

increased amounts of protein in your urine 
 Changes in blood levels of different salts or electrolytes 
 Increased amounts of cholesterol and triglyceride (blood fats) 
 High levels of sugar in your blood  
 
Common side effects (may affect up to 1 in 10 people) are:  
 Cancer and non-cancerous growths of the skin 
 Dangerous decrease of blood pressure which, if untreated, may lead to collapse, coma and death 
 Stroke 
 Dead tissue because of stopped blood supply 
 Liver inflammation (cytolytic hepatitis) 
 Damage to the kidney 
 Fluid in the lungs, wheezing, chest pain or angina, enlarged heart muscle (bottom of the heart) 
 Infection of the blood or tissues, respiratory infections, pneumonia, flu, sinus inflammation, runny 

nose, sore throat, pain in the mouth/throat region, herpes virus infections, shingles and other viral 
infections, mouth sores, thrush, kidney infection, fungal skin infections,fungal infections of the 
nails and other fungal infections, skin infection, infection of soft tissues, wound infection, 
infection limited to one area, slow healing, bloody bruise, build up of lymph fluid around the 
transplanted kidney 

 Fast heart rate, slow heart rate, abnormal and irregular heart beat, weak heart 
 Diabetes 
 Dehydration 



37 

 Inflammation of the stomach and intestines, usually caused by a virus 
 Upset stomach 
 Unusual sensation of pins and needles, numbness or weakness of the arms and legs 
 Rash, itching 
 Muscle pain, muscle weakness, bone pain, joint swelling, abnormal cartilage between bones of the 

spine, sudden inability to bend joint, muscle spasms, arthritis 
 Blockage of kidney blood vessels, enlarged kidney due to blockage of urine flow out of the 

kidney, backflow of urine from the bladder into the kidney tubes, inability to hold urine, 
incomplete emptying of the bladder, urinating at night, sugar in the urine 

 Increase in body weight, decrease in body weight 
 Cataract, increased blood congestion in the eye, blurred vision 
 Shaking or tremors, dizziness, fainting or passing out, ear pain, buzzing, ringing or other persistent 

noise in the ears 
 Acne, hair loss, abnormal change to the skin, excessive sweating, night sweats 
 Weakness/gap in abdominal muscles and out pouching of skin over healed incision, hernia on the 

stomach wall 
 Depression, fatigue, feeling of tiredness, drowsiness, or lack of energy, general feeling of being 

unwell, difficulty breathing when laying down, nose bleeding 
 Typical appearance of a person with high levels of steroids, such as moon face, hump back, upper 

body obesity 
 Abnormal collection of fluid 
Tests may show: 
 Low platelet counts in your blood, too many white blood cells, too many red blood cells 
 Changes in blood levels of carbon dioxide, fluid retention, low protein in the blood 
 Abnormal liver function tests, blood parathyroid hormone increased 
 Increased protein (c-reactive protein) in blood indicating inflammation 
 A decrease of antibodies (proteins that fight infection) in your blood 
 
Uncommon side effects (may affect up to 1 in 100 people) are:  
 Lung cancer, rectal cancer, breast cancer, a form of cancer in the bones, musles, or fat tissue, 

tumor of the skin and intestinal tract caused by a herpes virus and seen in patients with a 
weakened immune system, prostate cancer, cancer of the cervix, throat cancer, cancer of the 
lymph nodes, cancer of the bone marrow, cancer of the kidney, kidney tubes, or bladder 

 Fungal infection of brain, inflammation of the brain, serious brain infection called PML 
(progressive multifocal leukoencephalopathy)  

 Abnormal swelling of the brain, increased pressure inside the skull and brain, seizure, weakness 
causing loss of movement on one side of the body, loss of the covering around nerves, inability of 
muscles to move in the face 

 Any disease of the brain causing headache, fever, hallucinations, confusion, abnormal speech and 
body movement 

 Poor blood flow to the heart, blocked heart beats, abnormal aorta heart valve, abnormal rapid heart 
rate 

 Sudden problems with breathing leading to lung damage, increased blood pressure in the lungs, 
inflammation of the lungs, coughing up blood, abnormality of lungs and air tubes delivering air in 
and out of lungs, fluid in the sac around the lungs, breathing that stops temporarily during sleep, 
abnormal speaking sound 

 Genital herpes 
 Inflammation of the colon (large bowel) caused by the cytomegalovirus, inflammation of the 

pancreas, ulcer in the stomach, small intestines, or large intestine, blockage of the small intestine, 
black, tar-like stools, rectal bleeding, abnormal colour of the stool 

 Bacterial infections, inflammation or infection of the inner layer of the heart, tuberculosis, bone 
infection, inflammation of the lymph nodes, chronic dilation of the airways in the lungs with 
frequent lung infections 

 Infection with the strongyloides worm, diarrheal infection with Giardia parasite 
 Kidney disease that is caused by a virus (polyomavirus-associated nephropathy), inflammation of 

the kidneys, scarring of the kidneys, shrinkage of the small tubes in the kidney, inflammation of 
the bladder with bleeding 



38 

 Blood clotting in kidney artery 
 Guillian-Barré syndrome (a condition that causes muscle weakness or paralysis) 
 EBV (Epstein-Barr virus) lymphoproliferative disease 
 Blood clotting in veins, inflamed veins, periodic leg cramps 
 Abnormal arteries, scarring of the arteries, clotting in the arteries, narrowing of the arteries, 

temporary redness of the face/skin, swelling of the face 
 Stones in the gallbladder, fluid filled pocket in the liver, fatty liver 
 Skin disease with thickened patches of red skin, often with silvery scales, abnormal hair growth, 

excessive hair breakage, nails breaking, ulcer on the penis 
 Abnormal balance of minerals in the body causing bone problems, bone inflammation, abnormal 

weakening of the bone leading to bone problems, inflammation of the lining of the joints, rare 
bone condition 

 Inflammation of the testicles, an abnormally prolonged penile erection, abnormal cervical cells, 
breast mass, pain in the testes, ulcer in the female genital area, thinned vaginal walls, infertility or 
inability to become pregnant, swelling of the scrotum 

 Seasonal allergy 
 Poor appetite, loss of taste, decreased hearing 
 Abnormal dreams, mood swings, abnormal lack of ability to focus and sit still, difficulty 

understanding or thinking, poor memory, migraine, irritability 
 Numbness or weakness from poorly controlled diabetes, changes in the foot from diabetes, 

inability to keep legs still 
 Swelling of back of the eye causing changes in sight, eye inflamed, uncomfortable/increased 

sensitivity to light, swelling of the eyelid 
 Cracking of the corner of the mouth, swollen gums, salivary gland pain 
 Increased sexual desire 
 Burning sensation 
 Reaction to an infusion, scare tissue, inflammation, return of disease, feeling hot, ulcer 
 Not making enough urine 
 Failure of transplanted organ to work, problems during or after a transfusion, separation of the 

wound edges before it heals, broken bone, complete tear or separation of tendon, low blood 
pressure during or after a procedure, high blood pressure during or after a procedure, 
bruise/collection of blood within the soft tissues after a procedure, pain related to a procedure, 
headache related to a procedure, bruise of the soft tissue 

Tests may show: 
 Dangerously low red blood cells, dangerously lowered white cell counts, destruction of red blood 

cells, blood clotting problems, acid in the blood from diabetes, lack of acid in the blood 
 Improper production of hormones by the adrenal glands 
 Low vitamin D levels 
 Pancreatic enzymes in the blood increased, troponin levels in the blood increased, prostate-

specific antigen (PSA) increased, high uric acid levels in the blood, CD-4 lymphocyte cell counts 
decreased, low blood sugar 

 
Reporting of side effects 
If any of the side effects gets serious, please tell your doctor or pharmacist. This includes any possible 
side effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store NULOJIX 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the vial label and carton after EXP. 
The expiry date refers to the last day of that month. 
 
This medicine will be stored in the healthcare facility where it is administered.  



39 

 
Store in a refrigerator (2°C - 8°C). 
 
Store in the original package in order to protect from light. 
 
After reconstitution,  the reconstituted solution should be transferred from the vial to the infusion bag 
or bottle immediately.  
 
After dilution, and from a microbiological point of view, the product should be used immediately. If 
not used immediately, the solution for infusion may be stored in a refrigerator (2°C - 8°C) for up to 
24 hours. The solution for infusion may be stored for a maximum of 4 hours of the total 24 hours 
below 25°C. Do not freeze.  
The NULOJIX infusion must be completed within 24 hours of reconstitution of the powder. 
 
Do not use NULOJIX if you notice any particles or discolouration in the reconstituted or diluted 
solution. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What NULOJIX contains 
 
 The active substance is belatacept. Each vial contains 250 mg of belatacept. After reconstitution, 

each ml of concentrate contains 25 mg of belatacept. 
 The other ingredients are sodium chloride, sodium dihydrogen phosphate monohydrate, sucrose, 

sodium hydroxide (for pH adjustment) and hydrochloric acid (for pH adjustment). (See section 2) 
 
What NULOJIX looks like and contents of the pack 
 
NULOJIX powder for concentrate for solution for infusion (powder for concentrate) is a white to off-
white powder that can appear solid or broken into pieces.  
Each vial contains 250 mg belatacept. 
Packs of either 1 glass vial and 1  syringe or 2 glass vials and 2  syringes. 
 
Not all pack sizes may be marketed.  
 
Marketing Authorisation Holder and Manufacturer 
 
Marketing Authorisation Holder: 
Bristol-Myers Squibb Pharma EEIG 
Plaza 254 
Blanchardstown Corporate Park 2 
Dublin 15, D15 T867 
Ireland 
 
Manufacturer: 
Swords Laboratories T/A Bristol-Myers Squibb Cruiserath Biologics 
Cruiserath Road, Mulhuddart 
Dublin 15, D15 H6EF 
Ireland 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 



40 

Belgique/België/Belgien 
N.V. Bristol-Myers Squibb Belgium S.A. 
Tél/Tel: + 32 2 352 76 11 
 

Lietuva 
Bristol-Myers Squibb Kft. 
Tel: +370 52 369140  

България 
Bristol-Myers Squibb Kft. 
Teл.: + 359 2 4942 480 
 

Luxembourg/Luxemburg 
N.V. Bristol-Myers Squibb Belgium S.A. 
Tél/Tel: + 32 2 352 76 11 
 

Česká republika 
Bristol-Myers Squibb spol. s r.o. 
Tel: + 420 221 016 111 
 

Magyarország 
Bristol-Myers Squibb Kft. 
Tel.: +36 1 9206 550 

Danmark 
Bristol-Myers Squibb 
Tlf: + 45 45 93 05 06 
 

Malta 
BRISTOL-MYERS SQUIBB S.R.L. 
Tel: + 39 06 50 39 61 

Deutschland 
Bristol-Myers Squibb GmbH & Co. KGaA 
Tel: + 49 89 121 42-0 
 

Nederland 
Bristol-Myers Squibb B.V. 
Tel: + 31 (0)30 300 2222 

Eesti 
Bristol-Myers Squibb Kft. 
Tel: +372 640 1030 

Norge 
Bristol-Myers Squibb Norway Ltd 
Tlf: + 47 67 55 53 50 

Ελλάδα 
BRISTOL-MYERS SQUIBB A.E. 
Τηλ: + 30 210 6074300 
 

Österreich 
Bristol-Myers Squibb GesmbH 
Tel: + 43 1 60 14 30 
 

España 
BRISTOL-MYERS SQUIBB, S.A. 
Tel: + 34 91 456 53 00 
 

Polska 
BRISTOL-MYERS SQUIBB POLSKA SP. Z O.O. 
Tel.: + 48 22 2606400 
 

France 
Bristol-Myers Squibb SARL 
Tél: +33 (0)1 58 83 84 96 
 

Portugal 
Bristol-Myers Squibb Farmacêutica Portuguesa, 
S.A. 
Tel: + 351 21 440 70 00 

Hrvatska 
Bristol-Myers Squibb spol. s r.o. 
Tel: +385 1 2078 508 

România 
Bristol-Myers Squibb Kft. 
Tel: + 40 (0)21 272 16 00 
 

Ireland 
Bristol-Myers Squibb Pharmaceuticals uc 
Tel: + 353 (0)1 483 3625 
 

Slovenija 
Bristol-Myers Squibb spol. s r.o. 
Tel: +386 1 2355 100 

Ísland 
Bristol-Myers Squibb AB hjá Vistor hf. 
Sími: + 354 535 7000 
 

Slovenská republika 
Bristol-Myers Squibb spol. s r.o. 
Tel: + 421 2 20833 600 
 

Italia 
BRISTOL-MYERS SQUIBB S.R.L. 
Tel: + 39 06 50 39 61 
 

Suomi/Finland 
Oy Bristol-Myers Squibb (Finland) Ab 
Puh/Tel: + 358 9 251 21 230 
 



41 

Κύπρος 
BRISTOL-MYERS SQUIBB A.E. 
Τηλ: + 357 800 92666 
 

Sverige 
Bristol-Myers Squibb AB 
Tel: + 46 8 704 71 00 

Latvija 
Bristol-Myers Squibb Kft. 
Tel: +371 67708347 

United Kingdom 
Bristol-Myers Squibb Pharmaceuticals Ltd 
Tel: + 44 (0800) 731 1736 

 
This leaflet was last revised in 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
------------------------------------------------------------------------------------------------------------------------- 
 
The following information is intended for healthcare professionals only: 
 
 Use aseptic technique to make up the vials and dilute the solution for administration. 
 Use the silicone-free disposable syringe provided to make up the vials and to add the solution to 

the infusion. This will avoid aggregate formation. 
 Do not shake the vials. This will avoid foam formation. 
 The solution for infusion is to be used in conjunction with a sterile, non-pyrogenic, low protein 

binding filter (pore size of 0.2 µm to 1.2 µm). 
 
Dose selection and reconstitution of the vials 
Calculate the dose and number of NULOJIX vials required. Each NULOJIX vial provides 250 mg of 
belatacept. 
 Total dose of belatacept in mg equals the patient weight in kg times the belatacept dose in mg/kg 

(5 or 10 mg/kg, see section 3) 
 Dose modification of NULOJIX is not recommended for a change in body weight of less than 

10%. 
 Number of vials required equals the belatacept dose in mg divided by 250 rounded up to the next 

full number of vials.  
 Make up each vial with 10.5 ml reconstitution solution.  
 Volume of the reconstituted solution required (ml) equals total belatacept dose in mg divided 

by 25. 
 
Practical details on the reconstitution of vials 
Using aseptic technique, make up each vial with 10.5 ml of one of the following solvents (sterile water 
for injections, sodium chloride 9 mg/ml (0.9%) solution for injection or 5% glucose solution for 
injection), using the co-packed disposable syringe (necessary to avoid aggregate formation) and an 18-
21 gauge needle. Syringes are marked in units of 0.5 ml; therefore, the calculated dose should be 
rounded to the nearest 0.5 ml. 
 
Remove the flip off seal from the vial and wipe the top with an alcohol swab. Insert the syringe needle 
into the vial through the centre of the rubber stopper. Direct the stream of fluid to the glass wall of the 
vial and not into the powder. Remove the syringe and needle after 10.5 ml of reconstitution fluid has 
been added to the vial.  
 
To minimise foam formation, gently swirl and invert the vial for at least 30 seconds or until the 
powder is completely dissolved. Do not shake. Although some foam may remain on the surface of the 
reconstituted solution, a sufficient excess of belatacept is included in each vial to account for 
withdrawal losses. Thus, 10 ml of a 25 mg/ml belatacept solution can be withdrawn from each vial.  
 



42 

The reconstituted solution should be clear to slightly opalescent and colourless to pale yellow. Do not 
use if opaque particles, discolouration or other foreign particles are present. It is recommended to 
transfer the reconstituted solution from the vial to the infusion bag or bottle immediately. 
 
Practical details on the preparation of the solution for infusion 
After reconstitution, dilute the product to 100 ml with sodium chloride 9 mg/ml (0.9%) solution for 
injection or 5% glucose solution for injection. From a 100 ml infusion bag or bottle (typically, an 
infusion volume of 100 ml will be appropriate for most patients and doses, but total infusion volume 
ranging from 50 ml to 250 ml may be used), withdraw a volume of sodium chloride 9 mg/ml (0.9%) 
solution for injection or 5% glucose solution for injection equal to the volume (ml equals total dose 
in mg divided by 25) of the reconstituted NULOJIX solution required to provide the dose and discard 
it. Slowly add the required amount of reconstituted NULOJIX solution from each vial to the infusion 
bag or bottle using the same disposable syringe used for reconstitution of the powder. Gently mix the 
infusion container. The concentration of belatacept in the infusion should be between 2 mg and 10 mg 
belatacept per ml solution.  
 
Any unused portion in the vials must be discarded in accordance with local requirements. 
 
Administration 
When reconstitution and dilution are performed under aseptic conditions, the NULOJIX infusion 
should be started immediately or must be completed within 24 hours of reconstitution of the powder. 
If not used immediately, the solution for infusion may be stored in the refrigerator (2°C - 8°C) for up 
to 24 hours. Do not freeze. The solution for infusion may be stored for a maximum of 4 hours of the 
total 24 hours below 25°C. Infusion must be completed within 24 hours of reconstitution of the 
powder. Prior to administration, the solution for infusion should be inspected visually for particulate 
matter or discolouration. Discard the solution if any particulate matter or discolouration is observed. 
The entire, fully diluted infusion should be administered over a period of 30 minutes and must be 
administered with an infusion set and a sterile, non-pyrogenic, low protein binding filter (pore size of 
0.2 μm to 1.2 μm). Following administration, it is recommended that the intravenous line be flushed 
with infusion fluid to ensure administration of the complete dose. 
 
NULOJIX 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 coadministration of 
NULOJIX with other agents. 
 
Do not store any unused portion of the solution for infusion for reuse. 
 
Disposal 
Any unused product or waste material should be disposed of in accordance with local requirements. 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE ANDMANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETINGAUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE ANDEFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET