1. Name Of The Medicinal Product
NULOJIX
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
Each vial contains 0.65 mmol sodium.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Powder for concentrate for solution for infusion (powder for sterile 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) titers> 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
Adults
The recommended dose is based on patient body weight (kg). The dose and treatment frequency is given below.
Table 1: Dose of belatacept for renal transplant recipients
|
|
Dose for 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
|
Dose for 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.
Infusion-related reactions have been reported with belatacept administration in clinical studies. There were no reports of anaphylaxis on belatacept. 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%.
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 reconstituted 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.
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 (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 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 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
An increased incidence of graft thrombosis was observed in the post-transplant period in recipients of extended criteria donor allografts (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
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 titers often require increased immunosuppression. Belatacept has not been studied in patients with PRA titers > 30% (see section 4.2).
Belatacept has been administered with the following immunosuppressive agents in clinical studies: basiliximab, an MPA and corticosteroids.
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. In clinical studies, there were no reports of anaphylaxis. If any serious allergic or anaphylactic reaction occurs, NULOJIX therapy should be discontinued immediately and appropriate therapy initiated.
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). No formal interaction studies have been performed with belatacept.
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 Pregnancy And Lactation
Women of child-bearing potential/Contraception in males and females
Women of child bearing 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.
Breastfeeding
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 breastfeed while on treatment with a belatacept-based regimen.
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
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 (
The most commonly reported adverse reactions (
Adverse reactions resulting in interruption or discontinuation of belatacept in
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 (
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
Uncommon
|
blood immunoglobulin G decreased, blood immunoglobulin M decreased,
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, dysgeusia, cognitive disorder, memory impairment, migraine, burning sensation, diabetic neuropathy, restless leg syndrome
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Eye disorders
Common
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cataract, ocular hyperaemia, vision blurred
|
Uncommon
|
retinitis, conjunctivitis, eye inflammation, keratitis, photophobia, eyelid oedema
|
Ear and labyrinth disorders
Common
|
vertigo, ear pain, tinnitus
|
Uncommon
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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
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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
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Hepatobiliary disorders
Common
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cytolytic hepatitis, liver function test abnormal
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Uncommon
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cholelithiasis, hepatic cyst, hepatic steatosis
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Skin and subcutaneous tissue disorders
Common
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acne, pruritis, alopecia, skin lesion, rash, night sweats, hyperhidrosis
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Uncommon
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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
|
Common
|
renal tubular necrosis, renal vein thrombosis*, renal artery stenosis, glycosuria, hydronephrosis, vesicoureteric reflux, urinary incontinence, urinary retention, nocturia
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Uncommon
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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.
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.
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. 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%); two of these presented in the CNS.
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.
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.
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
|
|
