NULOJIX

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).

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. 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.

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.

1). 4). Infusion-related reactions have been reported with belatacept administration in clinical studies. 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%.

2). 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.

6.

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 […]

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. 8). 8). EBV serology should be ascertained before starting administration of belatacept.

3). 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.

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.

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. 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.

Transplant recipients who are Epstein-Barr virus (EBV) seronegative or serostatus unknown. 4).