Index of drugs

Prevention of graft rejection in recipients of allogeneic liver, kidney or heart transplants. Treatment of allogeneic graft rejection resistant to therapy with other immunosuppressive agents.

1 capsule contains 0.5 mg, 1 mg or 5 mg of tacrolimus. The preparation contains lactose.

An immunosuppressant from the macrolide group, a calcineurin inhibitor. It seems that the molecular level in the action of tacrolimus is mediated by binding to the cytosolic protein (FKBP12), responsible for the intracellular accumulation of the drug. The FKBP12-tacrolimus complex specifically and competitively binds to calcineurin and inhibits it, which leads to calcium-dependent inhibition of T-cell signaling pathways, thereby preventing the transcription of a separate set of cytokine genes. In particular, tacrolimus inhibits the formation of cytotoxic lymphocytes that are mainly responsible for transplant rejection. Tacrolimus inhibits T cell activation and B cell proliferation dependent on helper T cells, as well as the formation of lymphokines (such as interleukin-2, -3 and γ-interferon) and the expression of the interleukin-2 receptor. After oral administration, tacrolimus achieves C_max during 1-3 h. Bioavailability is 20-25%. The degree and speed of absorption of the drug is greatest if it is taken on an empty stomach. The presence of food (especially high-fat) reduces the rate and extent of absorption. There is a strong correlation between AUC and the minimum tacrolimus level in whole blood at steady-state, therefore monitoring these concentrations allows a good estimate of systemic drug exposure. In the circulatory system, tacrolimus is strongly associated with erythrocytes. To a significant extent (> 98.8%) is bound to plasma proteins. It is metabolized in the liver, mainly involving CYP3A4. It is also significantly metabolized in the intestinal wall. Several metabolites have been identified, of which only one showed under conditionsin vitro immunosuppressive effect similar to tacrolimus. T_0,5 tacrolimus is long and achieves different values. In healthy people, average T_0,5 in whole blood it is about 43 h. In adults with a transplanted liver is 11.7 h compared to 15.6 h in adult patients with a transplanted kidney. In children after T transplantations_0,5 drug is about 12.4 h. Increased clearance contributes to a shorter half-life in transplant recipients. The drug is excreted almost entirely as metabolites, mainly in the faeces; only 2% in the urine.

Hypersensitivity to tacrolimus or other ingredients. Hypersensitivity to other macrolides.

Due to the risk of cardiomyopathy (hypertrophy of the heart chambers or septum), patients (especially children) undergoing immunosuppressive therapy with a history of heart disease, hypertension, renal or hepatic impairment, infections, edema, fluid overload or receiving corticosteroids should be monitored using procedures such as cardiac echocardiography or ECG before and after transplantation (eg after 3 months, then after 9-12 months) - in the event of an abnormality, a dose reduction or change of the drug should be considered. Caution should be exercised in patients who have or have been suspected to have congenital QT prolongation. The use of other immunosuppressants, such as antilymphocytes, with tacrolimus increases the risk of lymphoproliferative disorders, so this combination therapy should not be used. The risk of lymphoproliferative disorders is increased in patients who do not have antibodies against the capsid antigen of the EBV virus, especially in young children (<2 years); in this group of patients, appropriate serological tests should be performed before starting treatment. In patients using immunosuppressive agents, including tacrolimus, there is an increased risk of opportunistic infections (bacterial, fungal, viral and protozoan), among others BK virus (nephropathy) and JC (progressive multifocal leukoencephalopathy - PML); this should be taken into account in the event of deteriorating renal function or neurological symptoms during therapy.If during treatment with tacrolimus, symptoms indicating the syndrome of posterior reversible encephalopathy (PRES) occur, such as: headache, mental state disorders, convulsions, blurred vision, a radiological examination (eg magnetic resonance imaging, MRI) should be performed; if PRES is diagnosed, it is recommended to maintain normal blood pressure, anticonvulsant therapy and immediate discontinuation of tacrolimus. In patients with severe hepatic impairment, the dose of tacrolimus may need to be reduced. Caution should be exercised when using tacrolimus with medicines with which it interacts. Clinical experience in patients who are not Caucasian and in patients with increased immunological risk (eg re-transplantation, the presence of anti-HLA antibodies) is limited. Due to the lactose content, the preparation should not be used in patients with rare galactose intolerance, Lapp lactase deficiency or malabsorption of glucose-galactose.

Due to the need for treatment, the use of tacrolimus in pregnant women may be considered if there are no safer medicines and when the expected benefit to the mother outweighs the potential risk to the fetus. The condition of the newborn should be monitored in the direction of adverse drug reactions (especially effects on the kidneys). There is a risk of premature birth (<37 weeks), as well as the risk of hyperkalemia in the newborn, which over time disappears spontaneously. Tacrolimus is excreted in human milk - women taking the preparation should not breast-feed. In rats, there was a detrimental effect on male fertility due to decreased sperm count and decreased sperm motility.

Very common: headache, tremor, diarrhea, nausea, renal dysfunction, hyperglycemic states, diabetes, hyperkalemia, hypertension, insomnia. Common: coronary heart disease, tachycardia, anemia, leukopenia, thrombocytopenia, leukocytosis, abnormal results of red blood cell tests, convulsions, disturbances of consciousness, paresthesias and sensory disturbances, peripheral neuropathies, dizziness, difficulties in writing, nervous system disorders, blurred vision, photophobia , eye diseases, tinnitus, dyspnoea, interstitial lung disease, pleural effusion, pharyngitis, cough, hyperemia and rhinitis, inflammation of the stomach and intestines, ulcer and perforation of the stomach and intestines, gastrointestinal haemorrhage, inflammation and mouth ulcers, ascites, vomiting, gastrointestinal pain, abdominal pain, signs and symptoms of indigestion, constipation, flatulence, bloating and distension, loose stools, gastrointestinal signs and symptoms, renal failure, acute renal failure, oliguria, renal tubular necrosis, toxic nephropathy, urinary tract abnormalities, bladder and urethral symptoms, pruritus, rash, alopecia, acne, increased sweating, joint pain, muscle cramps, limb pain, back pain, hypomagnesaemia, hypophosphatemia, hypokalemia, hypocalcemia , hyponatremia, hypervolaemia, hyperuricaemia, decreased appetite, lack of appetite, metabolic acidosis, hyperlipidemia, hypercholesterolemia, hypertriglyceridaemia, other electrolyte abnormalities, primary graft dysfunction, haemorrhage, thromboembolic and ischemic events, peripheral vascular disorders, vascular hypotension, conditions with weakness, disorders with fever, edema, pain and discomfort, increased alkaline phosphatase, increased body weight, impaired body temperature, abnormal liver enzymes, and improper liver function, cholestasis and jaundice, liver cell damage and hepatitis, cholangitis, symptoms of anxiety, confusion and disorientation, depression, depressed mood, mood disorders, nightmares, hallucinations, mental disorders. Uncommon: ventricular arrhythmias and cardiac arrest, heart failure, cardiomyopathy, ventricular hyperplasia, supraventricular arrhythmias, palpitations, abnormal ECG results, abnormal results of heart rate and pulse rate, coagulopathy, abnormal coagulation findings blood and bleeding, pancytopenia, neutropenia, coma, central nervous system haemorrhages and cerebrovascular accidents, paralysis and paresis,encephalopathy, speech and language disorders, amnesia, cataracts, hearing loss, respiratory failure, respiratory disorders, asthma, paralytic ileus, peritonitis, acute and chronic pancreatitis, increased blood amylase, gastroesophageal reflux disease, impaired gastric emptying anuria, haemolytic uraemic syndrome, dermatitis, photosensitivity, arthritis, dehydration, hypoproteinemia, hyperphosphatemia, hypoglycemia, infarction, deep vein thrombosis, shock, multi-organ failure, flu-like illness, temperature intolerance, tightness in the chest, feeling nervousness, abnormal well-being, increased activity of lactate dehydrogenase in the blood, reduced body mass, dysmenorrhoea and uterine bleeding, psychotic disorder. Rare: pericardial effusion, thromboemplate thrombocytopenia, hypoproterombinemia, increased tension, blindness, neuromuscular deafness, acute respiratory distress syndrome, sub-terminal condition, pancreatic pseudocyst, toxic epidermal necrosis, hirsutism, thirst, fall, ulceration, compression in the cage thoracic artery disease, decreased mobility, hepatic artery thrombosis, liver veno-occlusive disease. Very rare: abnormal echocardiogram, myasthenia gravis, impaired hearing, nephropathy, hemorrhagic cystitis, Stevens-Johnson syndrome, increased adipose tissue, liver failure, bile duct stenosis. Allergic and anaphylactoid reactions have also been observed. As with other potent immunosuppressants, patients receiving tacrolimus often have an increased risk of infection (viral, bacterial, fungal, protozoal). Existing infections may get worse. Both generalized and local infections may occur. In patients treated with immunosuppressants (including tacrolimus), cases of nephropathy associated with BK virus as well as cases of progressive multifocal leukoencephalopathy (PML) associated with JC virus infection have been reported. Patients receiving immunosuppressive therapy have an increased risk of malignant tumors. There is no known risk of secondary cancer with immunosuppressants, including tacrolimus. In association with the use of tacrolimus, the occurrence of benign and malignant tumors, including EBV-related lymphoproliferative disorders and skin malignancies, has been reported. There have been reports of misuse of the medicine, including unintentional, unintentional or unattended replacement of a tacrolimus formulation with rapid or prolonged release into another tacrolimus-containing formulation. Therefore, a number of cases of organ transplant rejection or other adverse events have been reported that may have been due to reduced or increased exposure to tacrolimus.

Treatment with the preparation requires careful monitoring by appropriately trained and equipped staff. Due to the risk of rejection of the transplanted organ or an increase in the frequency of adverse reactions due to clinically significant differences in systemic exposure to tacrolimus, the patient should receive one tacrolimus formulation (one release method) according to the corresponding daily dosing regimen; a change in the tacrolimus formulation (change in pharmaceutical form) or change in the dosage schedule should only take place under the careful supervision of a transplant specialist. When converting to any other tacrolimus-containing formulation, it is necessary to monitor blood levels of the drug and adjust the dose to ensure that systemic tacrolimus exposure remains unchanged. The starting dose recommendations given below should only be considered as a guide. The dosage of the preparation should be determined individually based on clinical assessment of rejection and tolerance of the transplant and monitoring of the concentration of the drug in the blood. Tacrolimus is routinely given at the same time as other immunosuppressive drugs in the initial post-operative period. The doses of the preparation, depending on the immunosuppressive regimen used, may vary.Liver transplantation. Prophylaxis of transplant rejection in adults: oral treatment with the product should be initiated at a dose of 0.1-0.2 mg / kg / day.Administration of the drug should be started about 12 hours after the completion of the surgery; if the patient's clinical status does not permit the oral dose, intravenous infusion should be initiated in a 24-hour continuous infusion at a dose of 0.01-0.05 mg / kg / day.Prophylaxis of transplant rejection in children: the initial oral dose is 0.3 mg / kg / day; if the patient's clinical status does not permit oral dosing, the drug should be administered intravenously in a 24-hour continuous infusion at a dose of 0.05 mg / kg / day.Dose adjustment in the post-transplant period in adults and children: the usual dose is reduced in the post-transplant period, in some cases the concomitant use of other immunosuppressants and the use of tacrolimus alone can be discontinued. Improvement in the patient's condition after organ transplantation may change the pharmacokinetics of tacrolimus and may require further dose adjustment.Therapy in transplant rejection in adults and children: in episodes of rejection, increased doses of the preparation, supplemental treatment with corticosteroids and short-term administration of mono- / polyclonal antibodies were used. If toxic effects are observed, the dose of tacrolimus may need to be reduced. If another drug is substituted for tacrolimus, treatment should start with the initial dose recommended for oral, primary immunosuppressive drugs.Kidney transplantation. Prophylaxis of transplant rejection in adults: oral treatment with the product should be initiated at a dose of 0.2-0.3 mg / kg / day. Treatment should be started within 24 hours of the end of the surgical procedure; if the patient's clinical status does not permit oral dosing, intravenous infusion should be initiated in a 24-hour continuous infusion at a dose of 0.05-0.10 mg / kg / day.Prophylaxis of transplant rejection in children: the initial oral dose is 0.3 mg / kg / day; if the patient's clinical status does not permit oral dosing, the drug should be administered intravenously over a 24-hour continuous infusion at a dose of 0.075-0.100 mg / kg / day.Dose adjustment in the post-transplant period in adults and children: the usual dose is reduced in the post-transplant period, in some cases the concomitant use of other immunosuppressants may be discontinued and tacrolimus and the other drug should be used. Improvement in the patient's condition after organ transplantation may change the pharmacokinetics of tacrolimus and may require further dose adjustment.Therapy in transplant rejection in adults and childrenIn increased episodes of rejection, increased doses of the preparation, supplemental treatment with corticosteroids and introduction of short-term administration of mono- / polyclonal antibodies were used. If toxic effects are observed, the dose of tacrolimus may need to be reduced. If another drug is substituted for tacrolimus, treatment should start with the initial dose recommended for oral, primary immunosuppressive drugs.Heart transplantation. Prophylaxis of transplant rejection in adults: tacrolimus can be used concurrently with antibody induction (allowing for later onset of tacrolimus treatment) or, alternatively, in clinically stable patients without antibody induction. After antibody induction, oral treatment with the product should be initiated at a dose of 0.075 mg / kg / day. Administration of the drug should be started within 5 days of the end of the surgical procedure, immediately after stabilization of the patient's clinical status. If the clinical condition of the patient does not permit oral dosing, intravenous infusion should be initiated in a 24-hour continuous infusion at a dose of 0.01-0.02 mg / kg / day. A different dosing regimen was also published, which involves the administration of tacrolimus orally within 12 hours after transplantation - this scheme was used in patients who had no evidence of organ failure (eg renal failure); in these cases, treatment was started with a starting dose of tacrolimus of 2-4 mg / day, co-administered with mycophenolate mofetil and corticosteroids or sirolimus and corticosteroids.Prophylaxis of transplant rejection in children: tacrolimus has been used with or without antibody induction. In patients without antibody induction, if tacrolimus therapy is started with intravenous administration, the recommended starting dose is 0.03-0.05 mg / kg / day in a 24-hour continuous infusion, until the tacrolimus blood 15-25 ng / ml.The route of administration should be changed to oral administration whenever possible from a clinical point of view. The first dose for oral treatment should be 0.3 mg / kg / day, and administration should be started 8-12 hours after discontinuing the intravenous infusion. After antibody induction, when tacrolimus administration is initiated orally, the recommended starting dose is 0.1-0.3 mg / kg / day.Dose adjustment in the post-transplant period in adults and children: the usual dose of the preparation decreases in the post-transplant period. Improvement in the patient's condition after organ transplantation may change the pharmacokinetics of tacrolimus and may require further dose adjustment.Therapy in transplant rejection in adults and childrenIn increased episodes of rejection, increased doses of the preparation, supplemental treatment with corticosteroids and introduction of short-term administration of mono- / polyclonal antibodies were used. In adult patients who have been switched from other medicines to tacrolimus, the initial oral dose is 0.15 mg / kg / day. In children who have switched to tacrolimus, the initial oral dose is 0.2-0.3 mg / kg / day.Therapy in transplant rejection, other allogenic transplants. The dosage recommended for lung, pancreas and intestine transplantation is based on limited data from prospective clinical trials. In lung transplant patients, tacrolimus was administered orally at an initial dose of 0.10-0.15 mg / kg / day, in patients after a pancreatic transplant with an initial oral dose of 0.2 mg / kg / day, and in patients after intestinal transplantation at an oral initial dose of 0.3 mg / kg / day.Dose adjustment in specific patient populations. In patients with severe hepatic impairment, it may be necessary to reduce the dose to maintain the lowest concentration in the blood within the recommended target range. Black patients may require higher doses to obtain effective concentrations than Caucasian patients. In general, children should be administered doses 1¹/₂-2 times higher than the dose used in adults to achieve similar concentrations in the blood. No dose adjustment is necessary in patients with renal impairment or in the elderly.Change from using cyclosporin: caution should be exercised when changing therapy based on ciclosporin to treatment based on the use of tacrolimus. Treatment with tacrolimus can be started after the measurement of ciclosporin blood concentration and assessment of the patient's clinical status. If blood levels of cyclosporin are increased, tacrolimus should be delayed. In practice, tacrolimus treatment starts 12-24 h after cessation of cyclosporin. After the change to the use of tacrolimus, the concentration of cyclosporin in the blood should be further monitored.Monitoring the concentration of the drug in the blood. The dosage of tacrolimus should be adjusted primarily based on the individual clinical assessment of rejection and tolerance of transplantation in individual patients along with the monitoring of the minimum concentration of tacrolimus in the blood. To aid in the evaluation of the optimal dosage, immunological methods are used to determine the concentration of tacrolimus in whole blood, including the semi-automated micro-molecular enzyme immunoassay (MEIA). After the transplantation, the minimum concentration of tacrolimus in the blood should be monitored. Minimum blood levels should be measured approximately 12 hours after dosing, immediately prior to the Next dose. The frequency of blood concentration determinations depends on clinical needs. Minimum blood levels should be measured approximately twice a week during the initial post-transplant period and then periodically during maintenance treatment; they should also be monitored after dose modification, after introducing changes to the immunosuppressant regimen and after concurrent administration of drugs that can change the concentration of tacrolimus in whole blood. Analysis of data from clinical trials suggests that in most patients, treatment success can be achieved when the tacrolimus blood trough level is maintained at <20 ng / ml. The clinical status of the patient should be taken into account when interpreting changes in drug concentrations in whole blood. In clinical practice, the minimal drug concentrations in whole blood were generally maintained in the range of 5-20 ng / ml in liver recipients and 10-20 ng / ml in renal and cardiac recipients in the early post-transplant period. Subsequently, during the maintenance period, blood levels generally remained between 5-15 ng / ml in patients with transplanted liver, kidney and heart.Way of giving. The daily dose of the preparation is always given orally in 2 divided doses (eg morning and evening). The capsules should be taken on an empty stomach or at least 1 hour before or 2-3 h after a meal, with a liquid (preferably water).