Index of drugs

Prophylaxis of transplant rejection in adult kidney transplant recipients with low or moderate immunological risk. It is recommended to initially use the preparation in combination with ciclosporin in a microemulsion and corticosteroids for 2 to 3 months. The preparation can be used in maintenance therapy in combination with corticosteroids only on the condition of gradual cessation of cyclosporin in the microemulsion.

1 tabl sugar-coated tablets or 1 ml of solution contain 1 mg of sirolimus.

Selective immunosuppressive drug. Sirolimus inhibits the activation of T lymphocytes induced by the majority of excitatory factors, by blocking intracellular signal transduction, dependent and independent of Calcium ions. The therapeutic effect of sirolimus depends on a different mechanism than the action of ciclosporin, tacrolimus and other immunosuppressive drugs. Sirolimus binds to the specific cytosolic protein FKPB-12, and the FKPB-12-sirolimus complex inhibits the activation of mammalian mTOR (a kinase essential for the course of the cell cycle). Inhibition of mTOR activity leads to blocking of some specific signal transduction pathways in the cell and ultimately to inhibiting lymphocyte activation leading to immunosuppression. After oral administration, sirolimus is rapidly absorbed, reaching C_max after 2 hours in patients after renal transplantation in the stabilization phase, receiving multiple doses. The therapeutic effect of both forms of the drug in kidney transplant recipients is the same. The systemic availability of sirolimus when combined with ciclosporin is approximately 14%. When repeatedly administered, the mean blood sirolimus concentration is increased by about 3-fold. The final elimination half-life of sirolimus in renal transplantation patients receiving multiple doses of oral medicinal product is 62 ± 16 h. However, the effective half-life is shorter and steady-state mean concentrations were obtained after 5-7 days. . Sirolimus penetrates very much into the morphing elements of the blood. It is a substrate of both CYP3A4 and P-glycoprotein. It is strongly metabolized in the O-demethylation and / or hydroxylation process. In human whole blood, sirolimus occurs mainly in the unchanged form, which in over 90% consists in the immunosuppressive activity of the drug. The drug is excreted mainly in the faeces, and only in about 2% - with urine.

Hypersensitivity to sirolimus or to any of the excipients.

Clinical experience with sirolimus in children and adolescents under 18 is insufficient - use is not recommended. The product has not been adequately tested in patients with high immunological risk. In patients with impaired hepatic function, close monitoring of the sirolimus trough levels in whole blood is recommended, in addition, in these patients, after administration of a loading dose or after a change in dosage, long-term therapeutic concentrations should be monitored until stable concentrations are achieved. In patients using immunosuppressive agents, including sirolimus, there is an increased risk of opportunistic infections (bacterial, fungal, viral and protozoan), among others virusPolyoma BK (causing nephropathy) andPolyoma JC (causing progressive multifocal leukoencephalopathy); this should be taken into account in the event of deteriorating renal function or neurological symptoms during therapy. The safety and efficacy of the preparation in immunosuppressive therapy in patients with transplanted liver or in patients with transplanted lungs has not been established - it is not recommended to use in this group of patients. In two clinical trials in patients with transplanted liverde novo the use of sirolimus in combination with ciclosporin or tacrolimus was associated with an increased incidence of hepatic artery thrombosis, leading in most cases to loss of transplantation or death.In hepatic transplant patients, there is no benefit in changing therapy based on a calcineurin inhibitor (CNI) for sirolimus-based therapy; the number of acute transplant rejection events over 12 months was significantly higher in the group after switching to sirolimus than in the group continuing treatment with CNI. In patients withde novo The use of sirolimus as a component of immunosuppressive therapy with lung transplantation led to the separation of anastomoses within the bronchi, in most cases fatal. The safety and efficacy of the change of calcineurin inhibitors to sirolimus has not been established in the maintenance treatment of kidney transplant recipients. Patients who were withdrawn from ciclosporin maintenance therapy had lower creatinine levels and a higher glomerular filtration rate, as well as lower incidence of malignant tumors than patients still on cyclosporine, and therefore no continuation of co-administration of ciclosporin with sirolimus can be recommended in supportive care. In patients with delayed graft function, sirolimus may delay restoration of renal function. In patients with BMI greater than 30 kg / m² pc. there may be an increased risk of abnormal wound healing. In patients with persistent hyperlipidaemia, a risk / benefit ratio should be considered before initiation of immunosuppressant therapy, including sirolimus; similar reassessment of the risk-benefit ratio of continuing therapy with the product should be performed in patients with severe hyperlipidemia. Caution should be exercised when co-administering other medicines with known adverse effects on renal function. The sirolimus tablets contain sucrose and lactose - in patients with fructose intolerance, galactose intolerance, glucose-galactose malabsorption, sucrase-isomaltase deficiency, Lapp lactase deficiency, the risk / benefit ratio should be evaluated before prescribing sirolimus tablets.

Do not use during pregnancy unless clearly necessary. During treatment with the preparation and within 12 weeks after its completion, effective contraception should be used. Breast-feeding should be discontinued during treatment.

Very common: urinary tract infections, thrombocytopenia, anemia, hypokalaemia, hypophosphatemia, hypercholesterolemia, hyperglycemia, hypertriglyceridaemia, headache, lymphoedema, hypertension, abdominal pain, diarrhea, constipation, nausea, acne, joint pain, peripheral edema, fever, pain, increased blood lactate dehydrogenase activity, increased blood creatinine. Common: sepsis, pneumonia, pyelonephritis, herpes simplex, fungal, viral and bacterial infections (such as infections caused bymycobacterium including tuberculosis, Epstein-Barr viruses, CMV, varicella zoster virus), skin cancer, thrombotic thrombocytopenic purpura or haemolytic uraemic syndrome, leukopenia, neutropenia, diabetes, tachycardia, deep vein thrombosis, pneumonia, pleural effusion, bleeding from nose, oral mucositis, ascites, changes in liver function tests, increased AST and ALT, rash, osteonecrosis, proteinuria, abnormal healing, edema, fever. Uncommon: lymphomas or hyperplasia of the lymphatic system after transplantation, pancytopenia, pericardial effusion (including haemodynamically significant exudate in children and adults), pulmonary embolism, pulmonary haemorrhage, pancreatitis, nephrotic syndrome. Rare: hypersensitivity reactions, including anaphylactic or anaphylactoid reactions, angioneurotic edema, exfoliative dermatitis, vasculitis caused by hypersensitivity, lymphoedema, alveolar cellular proteinosis. The consequence of immunosuppression may be increased susceptibility to infection and the possibility of developing lymphomas and other malignancies, especially of the skin. In patients using immunosuppressive agents, including sirolimus, cases of viral infection have been reportedPolyoma BK, causing nephropathy andPolyoma JC inducing multifocal leukoencephalopathy. Hepatotoxicity has been observed, the risk of which may increase with increasing blood trough levels. Fatal hepatic necrosis was rarely reported with increased levels of the minimum sirolimus in the blood.In patients undergoing immunosuppressive therapy, including those taking sirolimus, there have been cases of fatal interstitial lung disease (including pneumonia and, less frequently occurring, bronchiolitis obliterans with organized pneumonia and pulmonary fibrosis) in which the etiology was not recognized. infectious. Following the transplantation, cases of abnormal wound healing, including superficial wound dehiscence, rupture of anastomoses (eg wounds, vessels, airways, ureters, bile ducts) have been observed. In some patients, sperm parameters were observed when using the product. In patients with delayed graft function, sirolimus may delay restoration of renal function. The concomitant use of sirolimus and a calcineurin inhibitor may increase the risk of hemolytic uremic syndrome, thrombotic thrombocytopenia, thrombotic microangiopathy. Cases of focal, segmental glomerulosclerosis and cases of fluid accumulation, including peripheral edema, edema due to obstruction of lymphatic vessels, pleural effusion, pericardial effusion (including haemodynamically significant exudation in children and adults) have been reported.

Treatment with the preparation should be carried out by a specialist physician, suitably qualified in the field of transplantology.
Orally. Adults.Initial treatment (within 2-3 months after transplantation): the usual dosing regimen consists of administering a 6 mg loading formula as soon as possible after transplantation, followed by a 2 mg dose once a day. The dose of the preparation should be individually determined so that the minimum sirolimus concentrations in whole blood, determined before the Next dose, are within 4-12 ng / ml (determined by chromatography). Treatment with the preparation should be optimized, while gradually reducing the dose of corticosteroids and ciclosporin as a microemulsion. The recommended minimal concentrations of ciclosporin in the first 2-3 months after transplantation are 150-400 ng / ml (determination by monoclonal antibodies or other equivalent method).Maintenance treatment: within 4-8 weeks, cyclosporine should be gradually discontinued, while the dose of sirolimus should be modified so that the minimum blood levels in the whole blood are in the range of 12-20 ng / ml (determined by chromatography). Sirolimus should be given with corticosteroids. In patients for whom ciclosporin discontinuation was unsuccessful or could not be achieved, co-administration of ciclosporin and sirolimus should not be continued for more than 3 months after the transplant was performed. In these patients, in clinical cases, the preparation should be discontinued and an alternative immunosuppressive regimen should be implemented.
Limited data indicate that black patients require higher doses and maintain higher concentrations of sirolimus to achieve the same therapeutic efficacy as observed in patients of other breeds. There is insufficient data to determine whether the response to sirolimus in elderly patients (> 65 years) will differ from the response obtained in younger patients. No dosage adjustment is necessary for patients with impaired renal function. In patients with impaired liver function, the clearance of sirolimus may be reduced. In patients with severe hepatic impairment, it is recommended to reduce the maintenance dose by about half. There is no need to modify the loading dose of the preparation.
For optimal treatment with sirolimus, monitoring of its concentrations is required in all patients. Whole blood sirolimus concentrations should be closely monitored in the following patient populations: in people with hepatic impairment; when CYP3A4 inducers or inhibitors are co-administered and discontinued; if the dose of cyclosporin is significantly reduced or withdrawn. In the mentioned patient populations, there is the highest probability of having to use a special dosage. Optimally, the dosage should be determined based on the value of more than one minimal concentration, determined more than 5 days after the previous dose adjustment. Monitoring therapeutic concentrations can not be the only basis for modifying sirolimus therapy.Particular attention should be paid to signs and symptoms, tissue biopsies, and laboratory parameters. In order to minimize fluctuations in sirolimus concentrations, the preparation should be taken at the same time as the time of taking cyclosporine, after 4 hours from the administration of ciclosporin, consistently observing the intake of either on an empty stomach or during a meal. Patients can be switched to tablets containing an equivalent dose of sirolimus; however, it is recommended to measure a minimum concentration of 1-2 weeks after changing the form of the drug to confirm that the minimum concentrations are within the recommended range. After discontinuation of treatment with cyclosporine, the recommended trough levels of sirolimus are 12-20 ng / ml (determined by chromatography). On average, it is necessary to increase the dose of sirolimus 4 times after discontinuing cyclosporine. The rate of dose increase should correspond to the ciclosporin withdrawal rate. The maximum daily dose of sirolimus should not exceed 40 mg. If a loading dose is necessary in addition to the maintenance dose and therefore the planned daily dose exceeds 40 mg, the loading dose should be administered within 2 days. Minimum concentrations should be monitored for at least 3-4 days after administration of the loading dose (doses). In patients with severe hepatic impairment, after dose adjustment or after a loading dose, sirolimus concentrations should be monitored every 5-7 days until stable concentrations of sirolimus are reached in the 3 subsequent determinations, because of the prolonged period of time half-life steady state is reached with a delay.
To take the solution as a solution, use the dosing syringe; drug should be diluted in water or orange juice (for dilution do not use any other liquids including grapefruit juice); dilute the diluted solution and drink immediately. Swallow the tablets whole, do not chew or divide.