Index of drugs

Prophylaxis of transplant rejection in recipients of allogeneic liver, kidney or heart transplants. Treatment in cases of rejection of allogeneic graft resistant to therapy with other immunosuppressive drugs.

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

An immunosuppressant from the macrolide group, a calcineurin inhibitor. It seems that the action of tacrolimus on the molecular level 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, preventing transcription and activation of cytokine genes. In particular, tacrolimus inhibits the formation of cytotoxic lymphocytes, which are mainly responsible for transplant rejection. The drug inhibits T-cell activation and B-cell proliferation dependent on T-helper 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, maximum blood concentrations occur after about 1-3 hours. The average bioavailability is 20-25%. After oral administration of the drug (0.3 mg / kg / day), steady state concentrations were achieved within 3 days in the majority of patients after liver transplantation. The fastest rate and extent of tacrolimus absorption is obtained on an empty stomach. The presence of food reduces both the rate and extent of absorption of tacrolimus, the effect being most pronounced after meals rich in fat, less after meals rich in carbohydrates. There is a close correlation between the AUC and the steady state minimal concentration in whole blood. Therefore, monitoring the minimum concentrations in whole blood enables the correct assessment of systemic exposure. In the circulatory system, tacrolimus binds strongly to erythrocytes, therefore the ratio of drug concentration in whole blood to plasma concentration is approx. 20: 1. In plasma, tacrolimus is extensively (> 98.8%) bound to plasma proteins, mainly with albumin and α-1-glycoprotein. Tacrolimus is metabolised in the liver, mainly involving CYP3A4. It is also significantly metabolized in the intestinal wall. Several metabolites have been identified, of which only one is presentin 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 hours. In adults and children after liver transplantation, average T_0,5 is 11.7 and 12.4 h respectively, while in adult recipients, the kidney transplant is 15.6 hours. The observed prolongation of the period of excretion was the cause of a shorter T_0,5 at recipients. Most of the medicine is removed in the faeces, about 2% - with urine.

Hypersensitivity to tacrolimus or to other macrolides. Hypersensitivity to any of the excipients.

The following parameters should be routinely monitored during the initial post-transplantation period: arterial pressure, ECG, neurological condition, eyesight, fasting blood Glucose concentration, electrolytes (especially potassium), liver and kidney function tests, hematological parameters, blood coagulation parameters and protein concentration assays. in plasma. If clinically significant disorders are found, changes in the immunosuppressive therapy should be considered. If tacrolimus is used concomitantly, especially with potent CYP3A4 inhibitors or inducers, tacrolimus blood levels should be monitored to adjust the dose if necessary. The preparation containing St. John's wort should be avoided during treatment. Co-administration of ciclosporin and tacrolimus should be avoided, and caution should be exercised when using tacrolimus in patients who have previously received ciclosporin. Avoid taking high doses of potassium or potassium-sparing diuretics. Tacrolimus taken at the same time as some medicines with known nephrotoxicity or neurotoxicity may increase the risk of these effects.Immunosuppressive drugs can affect the response to vaccines and vaccination during tacrolimus therapy may be less effective. The use of vaccines containing live, attenuated microorganisms should be avoided. In the event of diarrhea, tacrolimus concentrations should be additionally monitored. In patients treated with the product, hypertrophy of the heart chambers or septum, described as cardiomyopathies, has been rarely observed. In most cases, these changes were transient and occurred when the lowest effective levels of tacrolimus in the blood were much higher than the recommended maximum concentrations. Other factors that increase the risk of these clinical conditions include pre-existing heart disease, use of corticosteroids, hypertension, renal or hepatic dysfunction, infection, fluid overload and edema. All high-risk patients undergoing significant immunosuppressive therapy should be monitored using procedures such as cardiac echocardiography or ECG in the period before and after transplantation (eg initially after 3 months and then after 9-12 months). In the event of an abnormality, consider reducing the dose of tacrolimus or replacing it with another immunosuppressant. Tacrolimus may prolong the QT interval, but there is currently no clear evidence of ventricular tachycardiatorsade de pointes. Caution should be exercised in patients who have or have been suspected to have congenital QT prolongation. The lymphoproliferative disorders associated with the Ebstein-Barr virus (EBV) have been observed in patients treated with tacrolimus. After conversion of treatment to tacrolimus, combination antilymphocyte therapy should not be used. In young children (<2 years) without EBV infection (EBV VCA capsid test negative) an increased risk of lymphoproliferative diseases has been reported - in this group of patients, prior to the use of tacrolimus, EBV VCA should be diagnosed. During the course of treatment, close monitoring of PCR results for EBV infection is recommended. A positive EBV PCR test may persist for several or a dozen months, but in itself does not determine the diagnosis of lymphoma or lymphoproliferative disease. There is no known risk of secondary cancer. During the application of the preparation There is a risk of skin malignancies - the exposure to sunlight and UV radiation should be limited by the use of clothing and sun creams with a high filtration coefficient. In patients treated with immunosuppressants, including tacrolimus, the risk of opportunistic infections (bacterial, fungal, viral and protozoan) increases. They also include infection with the BK virus and related nephropathy as well as infection with the JC virus and associated progressive multifocal leukoencephalopathy (PML). These infections often result from a high total immunosuppressive load and can lead to serious or fatal conditions, therefore in the differential diagnosis of deterioration of renal function or neurological symptoms in immunosuppressed patients, the above-mentioned infections should be considered. If patients taking tacrolimus develop symptoms suggestive of posterior reversible encephalopathy syndrome (PRES), such as headache, mental state disorders, convulsions or visual disturbances, imaging should be performed (eg by magnetic resonance imaging, MRI). If PRES has been diagnosed, it is recommended to maintain normal blood pressure and maintain seizure control and immediate discontinuation of the systemic use of tacrolimus. After taking proper care, most patients recover completely. Clinical experience in patients who are not Caucasian and in patients with increased immunological risk (eg re-transplantation, the presence of specific anti-HLA antibodies (PRA)) is limited. A dose reduction may be necessary in patients with severe hepatic impairment. The preparation contains lactose - should not be used in patients with rare hereditary galactose intolerance, lactase deficiency (Lapp type) or malabsorption of glucose-galactose.

The use of tacrolimus in pregnant women in the absence of safer medicines may be considered, and when the expected benefit outweighs the potential risk to the fetus. If the fetus is exposed to the medicine, the neonate should be monitored for adverse events of tacrolimus (especially effects on the kidneys).There is a risk of premature delivery before 37 weeks and the risk of hyperkalemia in the newborn, which over time disappears spontaneously. Tacrolimus is excreted in breast milk - women receiving the medicine should not breast-feed. In rat studies, the harmful effects of tacrolimus on male fertility (reduced sperm count and decreased sperm motility) have been observed.

Very common: headache, muscle tremors, diarrhea, nausea, renal dysfunction, diabetes, hyperglycemia, hyperkalemia, hypertension. Common: ischemic heart disease, tachycardia, anemia, leukopenia, thrombocytopenia, abnormal results of red blood cell tests, leukocytosis, convulsions, disturbances in consciousness, paresthesia and disordered sensation, peripheral neuropathy, dizziness, difficulties in writing, nervous system disorders, blurred vision, photophobia , eye diseases, tinnitus, shortness of breath, interstitial lung disease, pleural effusion, cough, pharyngitis, hyperemia and rhinitis, gastrointestinal signs and symptoms, vomiting, gastrointestinal pain and abdominal pain, stomach inflammation and intestines, gastrointestinal haemorrhage, ulceration and perforation of the stomach and intestines, ascites, inflammation and mouth ulcers, constipation, subjective and subjective symptoms of dyspepsia, flatulence, bloating and distension, loose stools, renal failure, acute renal failure , toxic nephropathy, dead kidney tubules, abnormal urine tests, oliguria, bladder and urethral disorders, rash, pruritus, alopecia, acne, sweating, joint pain, back pain, muscle cramps, limb pain, anorexia, metabolic acidosis, other electrolyte disturbances, hyponatremia, fluid retention, excessive uric acid in the blood, hypomagnesaemia, hypokalemia, hypocalcaemia, decreased appetite, increased blood cholesterol, hyperlipidemia, increased triglycerides, hypophosphatemia, primary transplantation disorders, thromboembolic and ischemic events, hypotension of peripheral origin, hemorrhage, peripheral vascular disease, febrile illness, pain and discomfort, weakness, edema, impaired body temperature, increased alkaline phosphatase, weight gain, incorrect results liver enzymes tests and abnormal liver function, biliary stasis (cholestasis) and jaundice, liver cell damage and hepatitis, cholangitis, symptoms of anxiety, confusion and confusion, depression, mood deterioration, mood disorders and disorders, nightmares, hallucinations, mental disorders. Uncommon: ventricular arrhythmias and cardiac arrest, heart failure, cardiomyopathies, supraventricular cardiac arrhythmias, ventricular hypertrophy, abnormal ECG, palpitations, abnormal heart rate and heart rate, coagulopathy, abnormal bleeding and blood clotting parameters , neutropenia, pancytopenia, coma, hemorrhagic stroke and cerebrovascular accident, paralysis and paresis, encephalopathy, speech and speech disorders, amnesia, cataracts, hearing loss, respiratory failure, respiratory disorders, asthma, acute and chronic pancreatitis, peritonitis, increased blood amylase, paralytic ileus , gastro-oesophageal reflux, impaired gastric emptying, haemolytic uraemic syndrome, anuria, dermatitis, photosensitivity, arthritis, dehydration, hypoglycaemia, hypoproteinemia, hyperphosphatemia, deep vein thrombosis, shock, infarction, multi-organ failure, flu-like symptoms, temperature intolerance, tightness in the chest, malaise, nervousness, increased blood lactate dehydrogenase, weight loss, dysmenorrhea, uterine bleeding, psychotic disorders. Rare: pericardial effusion, thromboedema, hypoprotrombinemia, increased tension, blindness, neuromuscular deafness, acute respiratory distress syndrome, gastrointestinal obstruction (subileus), pancreatic pseudocyst, toxic epidermal necrolysis (Lyell's syndrome), hirsutism, thirst, fall, ulcer, tightness in the chest, decreased mobility, liver veno-occlusive disease, hepatic artery thrombosis.Very rare: abnormal echocardiogram, muscle weakness, impaired hearing, nephropathy, bleeding cystitis, Stevens-Johnson syndrome, increased fat, liver failure, bile duct narrowing. Patients using tacrolimus often have an increased risk of infection (viral, bacterial, fungal, protozoal); existing infections may be exacerbated; Both generalized and local infections may occur. Cases of nephropathy associated with BK virus as well as cases of progressive multifocal leukoencephalopathy (PML) associated with JC virus infection have been reported. A number of cases of transplanted organ rejection (frequency unknown) have been observed as a result of misuse of the drug, including unintentional unintentional or unattended replacement of a tacrolimus formulation with rapid or prolonged release into another tacrolimus-containing formulation. Patients receiving immunosuppressive therapy have an increased risk of malignant tumors. 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. Allergic and anaphylactoid reactions have been observed in patients receiving tacrolimus.

Orally. Treatment with tacrolimus requires careful monitoring by suitably qualified and equipped staff. The drug can prescribe and change the immunosuppressive treatment only physicians with experience in the use of immunosuppressive drugs and handling patients after organ transplantation. The patient should receive one tacrolimus formulation in accordance with the corresponding daily dosing schedule; a change in the tacrolimus formulation or change in the dosage regimen should only take place under the careful supervision of a transplant specialist. When converting to any other tacrolimus-containing preparation, it is necessary to monitor blood levels of the drug and adjust the dose. The following starting dose recommendations should only be considered as a guide. The dosage of the drug should be determined individually based on the clinical assessment of rejection and tolerance of the transplant and monitoring of the concentration of the drug in the blood. If clinical signs of rejection occur, a change in immunosuppressive therapy should be considered. Tacrolimus can be administered intravenously or orally. In most cases, the treatment is initiated by oral route and, if necessary, by the contents of the capsule dissolved in water by the probe. In the initial postoperative period, tacrolimus is usually given in combination with other immunosuppressants. The dose of the drug is selected depending on the immunosuppressive regimen. It is recommended that the daily daily dose is administered in 2 divided doses (eg morning and evening). The capsules should be taken immediately after removal from the blister, they should be taken with liquid (preferably with water). Capsules should be administered on an empty stomach or at least 1 hour before or 2-3 h after a meal.Liver transplantation. Prophylaxis of transplant rejection in adults. Treatment should be initiated at a dose of 0.1-0.2 mg / kg / day, given in 2 divided doses (eg morning and evening). Administration of the drug should be started about 12 hours after the completion of the surgery. If the drug can not be administered orally due to the patient's clinical condition, intravenous therapy should be initiated at a dose of 0.01-0.05 mg / kg / day in a continuous 24-hour infusion.Prophylaxis of transplant rejection in children. Oral treatment starts with a dose of 0.3 mg / kg / day in 2 divided doses (eg morning and evening). If the patient's clinical condition prevents oral administration, treatment should be initiated at a dose of 0.05 mg / kg / day in a continuous 24-month infusion.Dosage modification in post-transplantation period in adults and children. In the post-transplant period, lower doses of tacrolimus are usually used. Occasionally, combination immunosuppressive therapy can be discontinued and tacrolimus monotherapy continued. Improvement in the patient's condition after transplantation may affect the pharmacokinetics of tacrolimus and may necessitate dose modification.Treatment of transplant rejection in adults and children. Increased doses of tacrolimus, supplemental corticosteroid therapy and short dosing cycles of mono- and polyclonal antibodies were used. In the event of toxicity (eg increased side effects), the dose of tacrolimus may need to be reduced.To convert another medicine to tacrolimus, tacrolimus treatment should be started with the oral dose recommended for initial immunosuppression.Kidney transplantation. Prophylaxis of transplant rejection in adults. Treatment with tacrolimus should be initiated at a dose of 0.2-0.3 mg / kg / day administered in 2 divided doses (eg morning and evening). Treatment should be started within 24 hours after completion of the surgery. If the drug can not be administered orally due to the patient's clinical condition, intravenous therapy should be initiated at a dose of 0.05-0.1 mg / kg / day in a continuous 24-hour infusion.Prophylaxis of transplant rejection in children. Oral treatment starts with 0.3 mg / kg / day administered in two divided doses (eg morning and evening). If the patient's clinical condition prevents oral administration, treatment should be initiated at a dose of 0.075-0.1 mg / kg / day in a continuous 24-month infusion.Dosage modification in post-transplantation period in adults and children. In the post-transplant period, lower doses of tacrolimus are usually used. Occasionally, combination immunosuppressive therapy may be discontinued and tacrolimus should be continued for dual therapy. Improvement in the patient's condition after transplantation may affect the pharmacokinetics of tacrolimus and necessitate additional dosage adjustment.Treatment of transplant rejection in adults and children. Increased doses of tacrolimus, supplemental corticosteroid therapy and short dosing cycles of mono- and polyclonal antibodies were used. In the event of toxicity (eg increased side effects), it may be necessary to reduce the dose of tacrolimus. To convert another medicine to tacrolimus, tacrolimus treatment should be started with the oral dose recommended for initial immunosuppression.Heart transplantation. Prophylaxis of transplant rejection in adults. Tacrolimus can be used after induction with antibodies (this enables later on the use of tacrolimus) or without antibody induction if the clinical condition of the patient is stable. Following oral antibody induction, tacrolimus therapy starts at a dose of 0.075 mg / kg / day in 2 divided doses (e.g. morning and evening). Dosage starts within 5 days after the end of the transplantation or after obtaining a stable clinical condition of the patient. If the clinical condition of the patient is prevented by oral dosing, administration of tacrolimus should be initiated at a dose of 0.01-0.02 mg / kg / day in a continuous 24-hour intravenous infusion. An alternative scheme was published in which oral tacrolimus treatment was started within 12 hours of transplantation, only in patients without organ disorders (eg renal dysfunction). Tacrolimus has been used orally at an initial dose of 2-4 mg / day in combination with mycophenolate mofetil and corticosteroids or in combination with sirolimus and corticosteroids.Prophylaxis of transplant rejection in children. Tacrolimus has been used after cardiac transplantation in children - with or without induction with antibodies. In the non-antibody-based regimen, if starting with intravenous therapy with tacrolimus, the recommended starting doses are 0.03-0.05 mg / kg / day in a continuous 24-hour infusion to achieve tacrolimus blood concentrations of 15-25 ng / ml. The conversion to oral treatment should be carried out as soon as the clinical condition of the patient allows. The first dose of oral therapy should be 0.3 mg / kg / day, starting 8-12 h after discontinuation of intravenous therapy. After oral antibody induction, tacrolimus therapy starts with a dose of 0.1-0.3 mg / kg / day in 2 divided doses (eg morning and evening).Dosage modification in post-transplantation period in adults and children. In the post-transplant period, lower doses of tacrolimus are usually used. Improvement in the patient's condition after transplantation may affect the pharmacokinetics of tacrolimus and necessitate additional dosage adjustment.Treatment of transplant rejection in adults and children. Increased tacrolimus doses supplemented with corticosteroid therapy and short dosing cycles of mono- / polyclonal antibodies were used. In adult patients, after switching from another medicine to tacrolimus, treatment starts with an oral dose of 0.15 mg / kg / day in 2 divided doses (eg morning and evening). In children, after switching from another medicine to tacrolimus, treatment starts with an oral dose of 0.2-0.3 mg / kg / day in 2 divided doses (eg morning and evening).Recommended dosage in the reaction of rejection of other allogeneic grafts. Dose recommendations for lung, pancreas and intestinal transplant rejection reactions were based on limited data from prospective clinical trials. Following transplantation, tacrolimus was administered at an initial oral dose of 0.1-0.15 mg / kg / day after transplanting the pancreas at an initial oral dose of 0.2 mg / kg / day and after intestinal transplantation at the initial oral dose 0.3 mg / kg / day.Recommended dosage in special patient groups. In patients with severe hepatic impairment, it may be necessary to reduce the dose.Renal function has no effect on the pharmacokinetics of tacrolimus - no dose adjustment is necessary. However, tacrolimus has potential nephrotoxicity and therefore careful monitoring of renal function is recommended (including studies such as serial serum creatinine, calculation of creatinine clearance, and monitoring of urine output). Compared to the Caucasians, black patients may require higher doses of tacrolimus to achieve the lowest effective drug concentrations. In order to obtain similar blood concentrations in children, doses of 1.5-2 times higher than those recommended for adults are generally used. Currently, there are no data available suggesting the need to adjust the dose in elderly patients.Replacement of cyclosporin with tacrolimus. Caution should be exercised when converting a cyclosporin regimen to tacrolimus treatment. Co-administration of cyclosporine and tacrolimus is not recommended. Before starting therapy with tacrolimus, the concentration of cyclosporin in the blood and the patient's clinical condition should be taken into account. If ciclosporin levels are elevated, treatment should be postponed. In practice, the administration of tacrolimus begins 12-24 hours after discontinuation of cyclosporin. Blood cyclosporin monitoring should continue as the clearance of cyclosporin after treatment conversion may change.Monitoring the therapeutic concentration of the drug. Dosing should be adjusted primarily based on individual clinical assessment of rejection and tolerance of transplantation in individual patients, supported by monitoring of the lowest effective concentration of tacrolimus in whole blood. In current clinical practice, whole blood concentrations are determined using immunological methods. During the post-transplantation period, the lowest effective concentration of tacrolimus in the blood should be monitored. For oral dosing, blood for the lowest effective concentration is collected 12 h after dosing just prior to the Next dose. The frequency of monitoring of the drug in the blood is selected depending on the clinical situation. Because the medicine has a small clearance, the change in blood levels may occur after a few days after dose modification. The lowest effective therapeutic concentration should be monitored approximately 2 times a week in the early post-transplant period and periodically during maintenance treatment. The lowest effective concentration of tacrolimus in the blood should also be monitored after changing the dosage, changing the immunosuppressive regimen or after adding drugs that can change the concentration of tacrolimus in whole blood. In the majority of patients, treatment success can be achieved when the lowest tacrolimus blood concentrations remain below 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 lowest effective drug concentrations in whole blood were generally between 5-20 ng / ml in liver recipients and 10-20 ng / ml in kidney and heart recipients in the early post-transplant period. During subsequent maintenance therapy, blood concentrations generally remained between 5-15 ng / ml in patients with transplanted liver, kidney or heart.