Index of drugs

Prophylaxis of transplant rejection in adult renal transplant patients, in combination with corticosteroids and mycophenolic acid (MPA). It is recommended to add an interleukin receptor (IL) -2 antagonist as an introductory treatment to the regimen using belatacept.

1 vial contains 250 mg belatacept (reconstituted 1 ml concentrate contains 25 mg belatacept); 1 vial contains 0.65 mmol sodium.

An immunosuppressive drug. Belatacept, a costimulatory blocker, is a soluble fusion protein composed of a modified extracellular domain of antigen-4 bound to a human cytotoxic T lymphocyte (CTLA-4) fused to a fragment (hinge-CH2-CH3 domain) of the Fc domain of a human immunoglobulin G1 antibody. Belatacept is produced using recombinant DNA technology in an expression system in mammalian cells. In the CTLA-4 ligand binding region, a substitution of two amino acids (L104 at E; A29 at Y) was introduced. Belatacept binds to CD80 and CD86 on antigen presenting cells. As a result, belatacept blocks the CD28-dependent co-stimulation of T lymphocytes, inhibiting their activation. Activated T cells are the main mediators of the immune response in a transplanted kidney. Belatacept, a modified form of CTLA4-Ig, binds to CD80 and CD86 more readily than the original CTLA4-Ig molecule from which it is derived. Increased affinity provides the appropriate level of immunosuppression necessary to counteract immune-dependent dysfunction and allograft rejection. Following the initial dose of belatacept, approximately 90% saturation of CD86 receptors on the surface of antigen presenting cells was observed in the peripheral blood. In the first month after transplantation, 85% saturation of CD86 was maintained. Up to 3 months after transplantation, CD86 saturation was maintained at about 70%, and after 12 months - at about 65%. Final T_0,5 belatacept after repeated infusion of intravenous doses of 5 and 10 mg / kg in kidney transplant patients is 8.2 (3.1-11.9) and 9.8 (6.1-15,1) days, respectively. With the recommended dosing schedule, serum concentrations usually reached steady-state before 8 weeks in the initial phase after transplantation and before the end of the 6th month in the maintenance phase. The minimum concentration of belatacept was maintained for up to 5 years after receiving the transplant. Minimal systemic accumulation of belatacept occurred after repeatedly, every 4 weeks, administration of doses of 5 or 10 mg / kg. in kidney transplant patients. The storage factor (accumulation) for belatacept at steady-state is 1.1.

Hypersensitivity to the active substance or to any of the excipients. Transplant recipients with a negative serological test for infection with the Epstein-Barr virus (EBV) or for whom the serological status is unknown.

Patients treated with belatacept had a higher incidence of lymphoproliferative disease after transplantation (PTLD) than patients treated with ciclosporin. Belatacept-treated transplant recipients who have a negative serological result for EBV infection are at increased risk for PTLD compared to patients with a positive EBV outcome. The serological status of EBV should be determined before the administration of belatacept. Other known risk factors for PTLD include cytomegalovirus (CMV) infection and PTLD T-lymphocyte depleting therapy in patients treated with belatacept most commonly related to o.u.n. Physicians should consider PTLD in differential diagnosis in patients with newly-diagnosed or worsening subjective and subjective neurological, cognitive or behavioral symptoms. The use of immunosuppressive drugs, including belatacept, may increase susceptibility to infections, including fatal infections, opportunistic infections, tuberculosis, and herpes infection. Prevention of CMV infection is recommended for at least 3 months after transplantation, particularly in patients with an increased risk of CMV infection. Prophylaxis of pneumonia caused byPneumocystis recommended for at least 6 months after transplantation.In clinical trials, tuberculosis was more frequently observed in patients receiving belatacept than in patients treated with ciclosporin. Most cases of tuberculosis have affected patients who have or have lived in countries with high prevalence of tuberculosis. Belatacept patients should be examined for tuberculosis and for latent infection with this disease before starting belatacept treatment. Before applying belatacept, appropriate treatment of latent tuberculosis should be implemented. Deep general immunosuppression is associated with an increased risk of progressive multifocal leukoencephalopathy (PML) - a rare, often rapidly progressing and death-related opportunistic infection o.u.n., which is caused by the JC virus. Physicians should consider PML in differential diagnosis in patients with newly-diagnosed or worsening subjective and subjective neurological, cognitive or behavioral symptoms. In case of suspected or confirmed PML, a neurological consultation is recommended. After the diagnosis of PML, it is recommended to reduce the dose or discontinue immunosuppressive drugs, taking into account the risk of transplant rejection. Plasmapheresis may accelerate the removal of the belatacept from the body. Patients receiving immunosuppressive therapy, including belatacept, are at increased risk of cancer, including skin cancer. Limit exposure to sunlight and ultraviolet (UV) by wearing protective clothing and using sunscreen with a high filter. In allograft donors with extended criteria, an increased incidence of transplanted thrombosis has been reported. The safety and efficacy of belatacept in hepatic transplant patients has not been established - its use is not recommended. In clinical studies, belatacept was given with the following immunosuppressants: basiliximab, MPA and corticosteroids. The concomitant administration of higher than recommended doses of immunosuppressive drugs should be avoided, as total exposure to immunosuppression is a risk factor for cancer and opportunistic infections. Lymphocyte-destroying therapies used to treat acute transplant rejection should be used with caution. Patients with high levels of anti-organisms (PRA) often require increased immunosuppression. Belatacept has not been studied in patients with PRA> 30%. Progressive dose reduction of corticosteroids in patients receiving belatacept should be performed with caution, particularly in patients with 4 to 6 non-compliance of human leukocyte antigens (HLA). After post-marketing use of belatacept in combination with induction of basiliximab, mycophenolate mofetil and reduction of the corticosteroid dose to 5 mg / day until 6th week after transplantation, an increased degree of acute rejection, in particular with a third degree of rejection; these grade 3 rejections occurred in patients with 4 to 6 HLA discrepancies. The corticosteroid dose reduction described above was faster than that used in clinical trials (for living donor or deceased donors that meet standard criteria, median median corticosteroid doses administered belatacept in the recommended schedule to 1, 3 and 6 months were 20 mg, 12 mg and 10 mg, respectively, in the case of organs from a donor with extended criteria, in the clinical trials median doses of corticosteroids given with belatacept in the recommended schedule, up to the 1st, 3rd and 6th months. , was 21 mg, 13 mg and 10 mg respectively). For patients who can be switched to another immunosuppressive drug, doctors should remember the 8-10 day half-life of belatacept to prevent under or over-immunosuppression after discontinuing belatacept. No anaphylaxis was reported in clinical trials. If a severe allergic or anaphylactic reaction occurs, discontinue administration and initiate appropriate treatment as soon as possible. Patients may be less effective during belatacept treatment. Vaccines containing live microorganisms should be avoided. There are theoretical concerns that belatacept treatment may increase the risk of developing autoimmune processes. Very few patients developed antibodies against the belatacept molecule and there was no clear correlation between the appearance of antibodies and the clinical response or side effects, but the data is too limited to make an unambiguous assessment of this phenomenon. The safety and efficacy of re-inclusion of belatacept have not been studied. When switching to belatacept again after prolonged discontinuation, the possible effect of belatacept antibodies present in the body should be considered, especially in patients who have not received continuous immunosuppressive therapy.The product contains 0.65 mmol or 15 mg sodium in a vial - this should be taken into account in patients on a controlled sodium diet. The safety and efficacy of the medicine has not yet been established in children and adolescents up to 18 years of age.

Belatacept should not be used in pregnant women unless clearly indicated. Women of childbearing potential should use effective contraception during belatacept treatment and up to 8 weeks after the last dose, as the potential risk of embryonic or fetal development is unknown. Patients should not breast-feed during treatment with belatacept.

Very common: urinary tract infection, upper respiratory tract infection, cytomegalovirus infection (CMV), bronchitis, anemia, leukopenia, hypophosphatemia, hypokalemia, dyslipidemia, hyperkalemia, hyperglycemia, hypocalcaemia, insomnia, anxiety, headache, hypertension, hypotension, dyspnoea, cough, diarrhea, constipation, nausea, vomiting, abdominal pain, joint pain, back pain, limb pain, proteinuria (proteinuria), increase in blood creatinine, dysuria, hematuria, peripheral edema, fever, impaired graft function. Common: sepsis, pneumonia, influenza, gastroenteritis, herpes zoster, sinusitis, herpes simplex, oral candidiasis, pyelonephritis, onychomycosis, BK polyoma virus infection, respiratory tract infection, yeast infection, runny nose, cellulitis , wound infection, local infection, herpes infection, fungal infection, fungal infection of the skin, squamous cell carcinoma, basal cell carcinoma, skin papilloma, thrombocytopenia, neutropenia, leukocytosis, polycythaemia, lymphopenia, reduction of immunoglobulin G in the blood, decrease in immunoglobulin M concentration blood, symptoms of Cushing's syndrome, weight gain, diabetes, dehydration, weight loss, acidosis, fluid retention, hypercalcemia, hypoproteinaemia, depression, tremor, paresthesia, cerebrovascular accident, dizziness, syncope, lethargy, peripheral neuropathy, cataract , przekr eye contact, blurred vision, labyrinthine dizziness, ear pain, tinnitus, tachycardia, bradycardia, atrial fibrillation, heart failure, angina pectoris, left ventricular hypertrophy, shock, infarction, hematoma, lymphocyte, angiopathy, arterial fibrosis, pulmonary edema, wheezing, hypocapnia, normal breathing only in a standing position, nosebleed, mouth and throat pain, dyspepsia (dyspepsia), aphthous stomatitis, abdominal hernia, cytolytic hepatitis, liver function tests, acne, pruritus, baldness , skin changes, rash, night sweats, excessive sweating, muscle pain, muscle weakness, bone pain, swelling of the joints, intervertebral disc disease, blockage of the joint, muscle spasms, osteoarthritis, renal tubule necrosis, renal vein thrombosis, renal artery stenosis , glycosuria, hydronephrosis, vesicoureteral reflux, n urinary incontinence, urinary retention, bedwetting, hydrocele, chest pain, fatigue, malaise, impaired healing, increased C-reactive protein, increased blood parathyroid hormone, chronic allograft (CAN), postoperative hernia. Uncommon: PML, fungal brain infection, CMV-induced intestinal inflammation, polyomavirus associated nephropathy, genital herpes infection, staphylococcal infections, endocarditis, tuberculosis, bronchiectasis, osteomyelitis, hirudoma, infectionBlastocystis, giardiasis, lymphangitis, lymphoproliferative disease associated with EBV infection, lung cancer, rectal cancer, breast cancer, sarcoma, Kaposi's sarcoma, prostate cancer, cervical cancer, larynx cancer, lymphoma, multiple myeloma, transitional cell carcinoma, monocytopenia, aplasia Pure red cell, agranulocytosis, hemolysis, hypercoagulation, hypogammaglobulinaemia, seasonal allergy, adrenal insufficiency, diabetic ketoacidosis, diabetic foot, alkalosis, decreased appetite, vitamin D deficiency, unusual dreams, mood instability, attention deficit hyperactivity disorder, increased libido, encephalitis , Guillain-Barre syndrome, cerebral edema, increased intracranial pressure, encephalopathy, convulsions, hemiparesis, demyelination, facial nerve palsy,taste disorders, cognitive impairment, memory impairment, migraine, feeling stimulated, diabetic neuropathy, restless legs syndrome, retinitis, conjunctivitis, inflammation of the eye, keratitis, photophobia, eyelid edema, hearing loss, acute coronary syndrome, atrio-ventricular block IIst. , aortic valve disease, supraventricular arrhythmia, venous thrombosis, arterial thrombosis, thrombophlebitis, arterial constriction, intermittent claudication, blood clots to the head, acute respiratory distress syndrome, pulmonary hypertension, pneumonia, hemoptysis, bronchopneumonia, painful breathing, exudate pleural hypnotic syndrome, dysphonia, mouth and throat sores, gastrointestinal disorders, pancreatitis, ulcerations of the large intestine, tar-like stools, gastric and duodenal ulcer, rectal haemorrhage, small intestine obstruction, inflammation of the lips, gingival hyperplasia, glandular pain salivary cholored stools, cholelithiasis, hepatic cyst, fatty liver, psoriasis, hypertrichosis in atypical places, nails breaking, penile ulceration, facial edema, hair fragility, bone metabolism disorders, osteoarthritis, bone thinning, synovitis, thrombosis renal artery, nephritis, cirrhosis, renal tubular atrophy, hemorrhagic cystitis, renal fibrosis, epididymitis, priapism, cervical dysplasia, breast tumor, testicular pain, vulvar ulcer, atrophic vulvovaginitis, infertility, scrotal edema, hypophosphatasia , infusion-related reactions (mostly hypotension, hypertension, flushing, headache - in most cases, they were not serious, mild to moderate, not recurrent), excitability, fibrosis, inflammation, disease relapse, feeling hot, ulcer, increase no pancreatic enzyme activity, increased troponin concentration, electrolyte disturbances, increased specific prostate antigen concentration, increased uric acid in the blood, decreased urine output, decreased blood Glucose, decreased CD4 lymphocyte count, transplant rejection, transfusion complications, dehiscence wounds, fractures, tendon rupture, hypotension after surgery, hypertension after surgery, hematoma after surgery, pain after surgery, headache after surgery, bruises. Very few patients developed antibodies against the belatacept molecule and there was no clear correlation between the appearance of antibodies and the clinical response or side effects, but the data is too limited to make an unambiguous assessment of this phenomenon. Autoimmune events have been reported rarely in clinical trials. In one patient treated with belatacept according to the MI scheme, the Guillian-Barré syndrome developed, which required discontinuation of therapy, and as a result resolved. Eventually, a number of reports from clinical trials suggest that long-term exposure to belatacept does not increase the predisposition and risk of developing autoimmune events.

Intravenously. Adults. Treatment should be prescribed and supervised by specialist doctors experienced in immunosuppressive therapy and in the management of kidney transplant patients. The drug has not been studied in patients with anti-organism (PRA) levels> 30% (who often require increased immunosuppression). Due to the risk of a high overall immunosuppression burden in these patients, the drug should only be used after consideration of an alternative treatment. The recommended dose is based on body weight.Dose in the initial phase. Transplant day, before 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 / kgDose in the maintenance phase. Every 4 weeks (± 3 days) starting from the end of the 16th week after transplantation: 5 mg / kg Patients do not require premedication before administering belatacept. Belatacept should be given in combination with the induction of basiliximab with mycophenolate mofetil and corticosteroids. Decreased corticosteroid dose should be introduced with caution, especially in patients with non-compliance of 4-6 human leukocyte antigens (HLA). Therapeutic monitoring of belatacept is not required. In clinical trials, the belatacept dose was not modified if the change in body weight was less than 10%.No dose adjustment is required in elderly patients or in patients with renal impairment or undergoing dialysis. Patients with hepatic impairment have not participated in kidney transplantation studies and therefore belatacept dose adjustments for such patients can not be recommended.Way of giving. The diluted reconstituted solution should be administered as an intravenous infusion at a relatively constant rate over 30 min. The infusion of the first dose should be given directly in the postoperative period or during surgery, but before the end of formation of vasomotor transplant anastomoses. After reconstitution and dilution of the drug under aseptic conditions, the preparation should be administered immediately or its administration must be completed within 24 hours after reconstitution of the powder. If the solution for infusion is not administered immediately, it can be stored in the refrigerator (2-8 ° C) for up to 24 hours. Do not freeze. The solution for infusion can be stored for a maximum of 4 of these 24 hours at a temperature below 25 ° C. The whole diluted infusion solution should be administered using a drip kit together with a sterile, non-pyrogenic, small-protein binding filter (0.2 μm to 1.2 μm pore size). After administration of the drug, it is recommended to rinse the IV tube with the infusion fluid to ensure that the entire dose is administered.