4.1. Therapeutic indications

NULOJIX, in combination with corticosteroids and a mycophenolic acid (MPA), is indicated for prophylaxis of graft rejection in adult recipients of a renal transplant (see section 5.1 for data on renal function).

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

Initiation at the time of transplantation

For transplant recipients receiving NULOJIX treatment from time of transplantation (“newly transplanted patients”), the addition of an interleukin-2 (IL-2) receptor antagonist is recommended.

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

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

6 mg/kg

For more details on the dose calculation, see section 6.6.

Patients do not require pre-medication prior to administration of belatacept.

At the time of transplantation, 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).

Conversion from a calcineurin inhibitor (CNI)-based regimen at least 6 months post-transplantation

For conversion from a CNI based to a NULOJIX based maintenance regimen in patients at least 6 months post-transplant, a dose of 6 mg/kg of NULOJIX administered every 2 weeks is recommended for the first 8 weeks, followed by the same dose every 4 weeks thereafter. Following initiation of therapy with NULOJIX, the calcineurin inhibitor should be continued, in tapering doses, for at least 4 weeks after infusion of the initial dose of NULOJIX (see section 5.1). More frequent monitoring for acute rejection is recommended, per local standard of care, for at least 6 months after conversion to NULOJIX (see section 4.4).

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.

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

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Post-transplant lymphoproliferative disorder (PTLD)

In Phase 2 and 3 studies (3 studies) in newly transplanted patients, 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 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).

Conversion from a CNI-based maintenance regimen

Conversion of clinically stable patients receiving a CNI-based maintenance regimen to a belatacept-based regimen may initially increase the risk of acute rejection. Closer monitoring for acute rejection is recommended for at least 6 months following conversion to belatacept, as per local standard of care. There are no data on conversion in patients considered to be at higher immunological risk as these were excluded from the conversion studies based on protocol defined criteria related to their previous rejection history (see section 5.1). Such patients may initially be at further risk of acute rejection following conversion to belatacept than those who were actually studied. In subjects with high immunological risk, conversion should only be considered when the potential benefits are anticipated to outweigh the risks.

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 9-10 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.

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.

Sodium Content

This medicinal product contains 0.55 mmol or 13 mg sodium per vial, equivalent to 0.64% of the WHO recommended maximum daily intake of 2 g sodium for an adult. 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.

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.

In trials conducted to support use in newly transplanted patients, 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 newly transplanted patient 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.

Table 2: Adverse reactions in newly transplanted patient 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, 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

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 newly transplanted patient Phase 3 studies, and a median of approximately 7 years in the newly transplanted patient Phase 2 study.

Long-term extension in Study 1 and Study 2

Of the 1209 randomised and newly 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.

Conversion Studies 1 and 2

The overall safety profile of belatacept in the two conversion studies was consistent with the known safety profile in the existing clinical population from the studies in newly transplanted patients presented in Table 2 above.

Description of selected adverse reactions

Malignancies and post-transplant lymphoproliferative disease

In the newly transplanted patient trials, 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.

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 newly transplanted patient 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

In newly transplanted patient trials, 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 in newly transplanted patient trials (%)

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 in newly transplanted patient trials, 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 newly transplanted 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 newly transplanted 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 in newly transplanted patients, 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).

In newly transplanted patient studies, 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 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 in newly transplanted patients. An additional 51 patients were treated for an average of 7 years in the long-term extension of a Phase 2 study in newly transplanted patients. 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 6 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

In newly transplanted patient studies, 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:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

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.