Index of drugs

Prophylaxis of transplant rejection in adults and children who are recipients of allogeneic kidney, liver or heart transplants. Treatment in cases of rejection of an allogeneic graft resistant to therapy with other immunosuppressant preparations in adults and children.

1 sachet contains 0.2 mg or 1 mg of tacrolimus (in the form of tacrolimus monohydrate). 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 transcription and activation of lymphokine 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 adjuvant 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. When administered as granules, tacrolimus absorbs quickly from the gastrointestinal tract, reaching C_max within 2-2.5 hours. The average bioavailability of tacrolimus capsules is 20% to 25% and is about 20% higher for granules. The presence of food reduces the rate and rate of absorption of the drug, especially after eating a meal with a high fat content. In the case of a meal with a high carbohydrate content, the effect of food on the absorption of the preparation is smaller. There is a close correlation between the AUC and the minimum steady-state drug concentration in whole blood, which makes it possible to assess systemic exposure to the drug. In the circulatory system, tacrolimus is strongly associated with erythrocytes. In plasma, a significant degree (> 98.8%) is associated with plasma proteins. 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 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 hours. Increased clearance contributes to a shorter half-life in transplant recipients. The drug is excreted almost completely in the form of metabolites, mainly in the faeces, only in 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, 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 concomitant use of other immunosuppressants such as anti-lymphocytic antibodies (eg basiliximab, daclizumab) increases the risk of lymphoproliferative disorders. The risk of lymphoproliferative disorders is increased in patients who do not have antibodies against the EBV capsid antigen; 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 othersBK virus (nephropathy) and JC (progressive multifocal leukoencephalopathy); this should be taken into account in the event of deteriorating renal function or neurological symptoms during therapy. If during treatment with tacrolimus, symptoms suggestive of posterior reversible encephalopathy (PRES) occur, such as: headache, mental state disorders, seizures, visual disturbances, imaging should be performed (eg magnetic resonance imaging, MRI); 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. There are no data on the safety of granules in critically ill patients who have been treated with tacrolimus in the form of a capsule or a prolonged release capsule (Prograf or Advagraf). 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: diabetes, hyperglycemia, hyperkalemia, insomnia, headache, muscle tremor, hypertension, diarrhea, nausea, abnormal liver function tests, renal dysfunction. Common: anemia, thrombocytopenia, leukopenia, non-standard results of red blood cell tests, leukocytosis, anorexia, metabolic acidosis, other electrolyte disturbances, hyponatraemia, fluid retention, excessive uric acid in the blood, hypomagnesaemia, hypokalemia, hypocalcaemia, decreased appetite , increased blood cholesterol, hyperlipidemia, increased triglycerides, hypophosphatemia, confusion and confusion, depression, anxiety symptoms, hallucinations, mental disorders, mood depression, mood disorders, nightmares, nervous system disorders, seizures, disturbances of consciousness, peripheral neuropathy , dizziness, paresthesia and disorder, difficulty in writing, eye diseases, blurred vision, photophobia, tinnitus, ischemic heart disease, tachycardia, thromboembolic and ischemic events, hypotension, hemorrhage, vasculitis eczema, interstitial lung disease, dyspnea, pleural effusion, cough, pharyngitis, hyperemia and rhinitis, gastrointestinal and physical symptoms, vomiting, gastrointestinal pain and abdominal pain, stomach and intestinal inflammation, gastrointestinal haemorrhage or intestines, 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, bile duct disorders, damage to liver cells and hepatitis, cholestasis and jaundice, rash, pruritus, alopecia, acne, hyperhidrosis, joint pain, back pain, muscle cramps, limb pain, kidney failure, acute renal failure, toxic nephropathy, kidney tubule necrosis, abnormal urine test results, oliguria, disorder bladder and urethra, fever, and pain feeling well, weakness, edema, impaired body temperature, increased alkaline phosphatase, weight gain, and graft function abnormalities.Uncommon: coagulopathy, pancytopenia, neutropenia, non-normalizing parameters of bleeding and blood coagulation, dehydration, hypoglycaemia, hypoproteinemia, hyperphosphatemia, psychotic disorders, encephalopathy, central nervous system hemorrhagic stroke and cerebrovascular accident, coma, speech and gloating disorders, paralysis and paresis, amnesia, cataracts, hearing loss, heart failure, ventricular arrhythmias and cardiac arrest, cardiac arrhythmias of supraventricular origin, cardiomyopathies, abnormal ECG, ventricular hypertrophy, palpitations, abnormal heart rate and heart rate, thrombosis deep vein limbs, shock, infarction, respiratory failure, respiratory disorders, asthma, acute and chronic pancreatitis, peritonitis, increased blood amylase, paralytic ileus, gastro-oesophageal reflux, disordered emptying no stomach, dermatitis, hypersensitivity to light, arthritis, hemolytic uremic syndrome, anuria, dysmenorrhea, uterine bleeding, weight loss, flu-like symptoms, increased lactate dehydrogenase activity, nervousness, malaise, multi-organ failure, feeling tightness in the chest, temperature intolerance. Rare: thrombotic thrombocytopenic purpura, hypoproterombinemia, hirsutism, increased tension, blindness, neuromuscular deafness, pericardial effusion, acute respiratory distress syndrome, pancreatic pseudocyst, gastrointestinal hypertension, embolic hepatic venous thrombosis, hepatic artery thrombosis, toxic epidermal necrolysis , fall, sores, tightness in the chest, decreased mobility, thirst. Very rare: muscle fatigue, impaired hearing, abnormal echocardiogram, liver failure, Stevens-Johnson syndrome, nephropathy, hemorrhagic cystitis, increased fat. Allergic and anaphylactoid reactions were also 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 in accordance with the corresponding daily dosing regimen; 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 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. In the initial postoperative period, the preparation is routinely administered with other immunosuppressive drugs. 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.Careful and frequent monitoring of the lowest effective concentration of tacrolimus during the first 2 weeks after transplantation is recommended to ensure that systemic exposure directly after transplantation is sufficient. Because tacrolimus is a substance with low clearance, adjusting the dose may take up to several days before a constant blood level is obtained. If clinical rejection symptoms occur, a change in immunosuppressive therapy should be considered.
Prophylaxis of kidney transplant rejection. Adults: treatment should start with a dose of 0.2-0.3 mg / kg / day given in 2 divided doses (eg morning and evening). Treatment should be started within 24 hours of the end of the surgical procedure. If the clinical condition of the patient does not permit oral dosing, intravenous administration at a dose of 0.05-0.1 mg / kg / day (Prograf 5 mg / ml concentrate for solution for infusion) should be initiated as continuous infusion lasting 24 hours. h.Children: treatment should be started at a dose of 0.3 mg / kg / day administered in 2 divided doses (eg morning and evening). If the clinical condition of the patient does not permit oral dosing, intravenous administration at an initial dose of 0.075-0.1 mg / kg / day (Prograf 5 mg / ml concentrate for solution for infusion) should be initiated as continuous infusion lasting 24 h .Dose adjustment in the post-transplant period in adults and children: the usual dose is reduced during the post-transplant period, in some cases the concomitant use of other immunosuppressants may be discontinued and tacrolimus-based dipia therapy should be used. Changes in the patient's condition after organ transplantation may change the pharmacokinetics of tacrolimus and may require further dose adjustment.Prophylaxis of liver transplant rejection. Adults: treatment should start with a dose of 0.1-0.2 mg / kg / day administered in 2 divided doses (eg morning and evening). Treatment should be started about 12 hours after the surgery. If the clinical condition of the patient does not permit oral dosing, intravenous administration at a dose of 0.01-0.05 mg / kg / day (Prograf 5 mg / ml concentrate for solution for infusion) should be initiated by continuous infusion of 24 h.Children: treatment should be started at a dose of 0.3 mg / kg / day administered in 2 divided doses (eg morning and evening). If the clinical condition of the patient does not permit oral dosing, intravenous administration at an initial dose of 0.05 mg / kg / day (Prograf 5 mg / ml concentrate for solution for infusion) should be initiated as continuous infusion lasting 24 hours.Dose adjustment during the post-transplant period in adults and children: usually the dose is reduced during the post-transplant period, in some cases the concomitant use of other immunosuppressants and the use of tacrolimus-based monotherapy may be discontinued. Improvement in the patient's condition after organ transplantation may change the pharmacokinetics of tacrolimus and may require further dose adjustment.Prophylaxis of heart transplant rejection. 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 administered in 2 divided doses (eg morning and evening). 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 administration at a dose of 0.01-0.02 mg / kg / day (Prograf 5 mg / ml concentrate for solution for infusion) should be initiated by continuous infusion of 24 h. A different dosing schedule was also published, which consists of administering tacrolimus orally within 12 hours of transplantation - this scheme was used only in patients who did not have 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.Children: tacrolimus has been used with or without antibody induction. In patients without antibody induction, if tacrolimus therapy starts with intravenous administration, the recommended starting dose is 0.03-0.05 mg / kg / day (Prograf 5 mg / ml concentrate for solution for infusion) by continuous infusion for 24 hours until reaching a concentration of tacrolimus in whole blood of 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 discontinuation of the infusion.After antibody induction, when tacrolimus is administered orally, the recommended starting dose is 0.1-0.3 mg / kg / day in 2 divided doses (eg morning and evening).Dose adjustment during the post-transplant period in adults and children: usually the dosage 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.Change of treatment with a granular preparation (Modigraf) for a capsule preparation (Prograf). In stable allogeneic patients treated with tacrolimus in the form of granules, in whom a change to treatment with a capsule formulation (Prograf), also taken twice daily, the basic daily dose should remain in the ratio 1: 1 (mg: mg). If this is not possible, the total daily dose of Prograf should be rounded up to the closest dose possible to administer; Most of the dose is given in the morning and smaller in the evening. Similarly, in patients who have changed treatment with Prograf capsules for treatment with Modigraf granules, the total daily dose of Modigraf should be the same as the total daily dose of Prograf. If it is not possible to change the treatment at the same dose, the total daily dose of Modigraf should be rounded down to the nearest daily full dose possible with the 0.2 mg and 1 mg sachets. The total daily dose of Modigraf granules should be administered in two equal doses. If it is not possible to take even doses, the larger dose is taken in the morning and the lower dose in the evening. It is not allowed to use only part of the contents of the Modigraf packet. The lowest effective levels of tacrolimus in blood should be determined prior to the change of treatment and within 1 week after the change of therapy; the dose should be adjusted to ensure that similar systemic drug exposure is maintained. Change in treatment with ciclosporin for tacrolimus treatment. Caution should be exercised when switching from ciclosporin to tacrolimus. Co-administration of these medicines is not recommended. 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.Treatment in allograft rejection. In rejection episodes, increased doses of tacrolimus, supplemental treatment with corticosteroids, and short-term administration of mono- / polyclonal antibodies were used. If your side effects get worse, you may need to lower the dose of tacrolimus.Kidney or liver transplantation. In both adults and children, when switching from other immunosuppressants to tacrolimus in a 2-pg granule, treatment should begin with the oral initial dose recommended in primary immunosuppression.Heart transplantation: in adult patients, after changing the therapy for the use of granules, treatment should start at a dose of 0.15 mg / kg / day, given in 2 divided doses (morning and evening). In children after switching to tacrolimus, treatment should be started with an oral starting dose of 0.2-0.3 mg / kg / day administered in 2 divided doses (eg morning and evening).Other allogenic transplants: lack of clinical experience in the use of tacrolimus in granules (Modigraf) in patients after lung, pancreas or intestine transplantation. Prograf was used orally at a starting dose of 0.1-0.15 mg / kg / day in patients after a transplant, 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 effective blood concentration of tacrolimus within the recommended target range. No dose adjustment is necessary in patients with renal impairment or in the elderly. 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.Monitoring the concentration of the drug in the blood. Dosage should be adjusted primarily based on individual clinical assessment of rejection and tolerance of transplantation in individual patients along with the monitoring of the lowest effective concentration of tacrolimus in the blood.The immunological methods to determine the concentration of tacrolimus in whole blood are used as an aid in the assessment of optimal dosing. The lowest effective blood levels should be measured approximately 12 h after dosing, immediately prior to the Next dose. The frequency of blood concentration determinations depends on clinical needs. The lowest blood concentrations should be measured about twice a week in the initial period after transplantation and then periodically during maintenance treatment; they should also be monitored when clinical signs of toxicity or acute transplant rejection are observed, when switching from Modigraf to Prograf kaps. after dose adjustment, changes in immunosuppressive therapy, and after co-administration of compounds that may alter the concentration of tacrolimus in full blood. Analysis of data from clinical trials suggests that in most patients, treatment success can be achieved when the lowest effective concentrations of tacrolimus in the blood stay 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 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.
The daily dose is given orally 2 times a day, in the morning and in the evening. In general, tacrolimus therapy starts with oral administration. If desired, the dosage of tacrolimus can be started by administering the granules, after being suspended in water, through the nasogastric tube. For maximum absorption, the granules should be taken on an empty stomach or at least 1 hour before or 2-3 hours after a meal. The required dose is determined based on the patient's body weight, using the smallest possible number of sachets. The suspension (max. 50 ml, depending on body weight) is prepared in a cup using 2 ml of water (at room temperature) for 1 mg of tacrolimus. PVC dishes should not be used. The granules are added to water and mixed. It is not recommended to use other liquids or dishes to empty the sachets. The suspension can be given after pulling it into the syringe or swallowing it directly. It has a sweet taste due to the lactose content. The cups should then be rinsed once with the same amount of water used to prepare the slurry and drink water. The suspension should be administered immediately after preparation. If the patient's condition does not allow oral medication immediately after transplantation, tacrolimus therapy can be started by intravenous administration (see SPP Prompt 5 mg / ml, concentrate for solution for infusion) at a dose of approximately¹/₅ the recommended oral dose in a given indication.