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 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) > 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
 

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. 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 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 preva lence of tuberculosis. Patients should be eva luated 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,