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 medicinal products.

1 amp. (1 ml) contains 5 mg of tacrolimus. The product contains cured polyoxyethylated castor oil and dehydrated ethanol.

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. In humans, distribution of tacrolimus after intravenous infusion was described as two-phase. In the circulatory system, tacrolimus is strongly associated with erythrocytes. To a significant extent (> 98.8%) is bound to plasma proteins. 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 and children with a transplanted liver, it is 11.7 h and 12.4 h respectively, compared to 15.6 h in adult patients with a transplanted kidney. Increased clearance contributes to a shorter half-life in transplant recipients. Tacrolimus is metabolised in the liver, mainly involving cytochrome P450-3A4. 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. 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 macrolides and to the rest of the preparation (especially to polyoxyethylene hydrogenated castor oil or similar substances).

Due to the risk of cardiomyopathy (hypertrophy of the heart chambers or septum), patients undergoing immunosuppressive therapy with a history of cardiac disease, taking corticosteroids, with hypertension, renal or hepatic impairment, infections, edema, overloaded fluids, as well as small children and patients with significant the degree of immunosuppression 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. In patients treated with the preparation, lymphoproliferative disorders associated with EBV have been observed. In patients who have had a change to treatment with the product, antilymphocytic therapy should not be used at the same time. The risk of lymphoproliferative disorders is increased in very young children (<2 years of age) who do not have antibodies against the EBV capsid antigen; in this group of patients, appropriate serological tests should be performed before starting treatment. If during treatment with tacrolimus, symptoms suggestive of a posterior reversible encephalopathy syndrome (PRES) occur, such as: headache, mental state disorders, convulsions, visual disturbances, imaging should be performed (eg magnetic resonance imaging, MR); if PRES is diagnosed, it is recommended to maintain normal blood pressure, anticonvulsant therapy and immediate discontinuation of the drug. 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. Accidental administration to the artery or perivascular wall can cause irritation at the injection site. The cured polyoxyethylene castor oil contained in the preparation may cause anaphylactoid reactions - care should be taken in patients who previously received products containing derivatives of this substance and in patients prone to allergies by intravenous injection or infusion. The risk of anaphylaxis can be reduced by administering the product in a slow infusion or by prior administration of an antihistamine.

Due to the need for treatment, the use of tacrolimus in pregnant women may be considered if there is a lack of safer medicines and when the expected benefits outweigh 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. Women taking the product should not breastfeed. In rats, a harmful effect on male fertility has been observed.

Very common: muscular tremor, headache, diarrhea, nausea, renal dysfunction, hyperglycemia, diabetes, hyperkalemia, hypertension, insomnia. Common: coronary heart disease, tachycardia, anemia, leukopenia, thrombocytopenia, leukocytosis, abnormal results of red blood cell tests, seizures, disturbances of consciousness, paresthesia and disorder of sensation, peripheral neuropathy, dizziness, difficulty writing, disorders of the nervous system, blurred vision, photophobia, eye diseases, tinnitus, shortness of breath, interstitial lung disease, pleural effusion, pharyngitis, cough, hyperemia and rhinitis, inflammation, ulceration and perforation of the stomach and intestines, gastrointestinal haemorrhage, inflammation and mouth ulcer, ascites, vomiting, gastrointestinal pain and abdominal pain, indigestion, constipation, flatulence, bloating and distension, loose stools, signs and symptoms of gastrointestinal intestinal disease, kidney failure, acute renal failure, oliguria, renal tubule necrosis, toxic nephrop atia, abnormal urine tests, bladder and urethral disorders, pruritus, rash, alopecia, acne, excessive sweating, joint pain, muscle cramps, limb and back pain, hypomagnesaemia, hypophosphatemia, hypokalemia, hypocalcemia, hyponatremia, fluid retention in the body , excessive concentration of uric acid in the blood, decreased appetite, anorexia, metabolic acidosis, hyperlipidemia, increased blood cholesterol, increased triglycerides, other electrolyte disturbances, transplantation disorders, haemorrhage, thromboembolic and ischemic events, peripheral vascular disease, hypotension peripheral origin, weakness, fever, edema, pain and discomfort, increased alkaline phosphatase, weight gain, impaired body temperature, liver dysfunction and abnormal liver enzymes, stagnation of the liver you and jaundice, hepatocellular damage and hepatitis, cholangitis, anxiety symptoms, confusion and disorientation, depression, depressed mood, mood disorders, nightmares, hallucinations, mental disorders. Uncommon: ventricular arrhythmias and cardiac arrest, heart failure, cardiomyopathy, ventricular hypertrophy, supraventricular cardiac arrhythmias, palpitations, abnormal ECG, abnormal heart rate and heart rate, coagulopathy, non-standard parameters blood clotting and bleeding, pancytopenia, neutropenia, coma, central nervous system hemorrhagic stroke and cerebrovascular accident, paralysis and paresis, encephalopathy, speech and speech disorders, amnesia, cataracts, hearing loss, respiratory failure, respiratory disorders, asthma, paralytic ileus intestines, peritonitis, acute and chronic pancreatitis, increased blood amylase, gastro-oesophageal reflux, impaired gastric emptying, anuria, haemolytic uraemic syndrome, dermatitis, photosensitivity, arthralgia, dehydration .hypoproteinemia, hyperphosphatemia, hypoglycemia, infarction, deep vein thrombosis, shock, multi-organ failure, flu-like symptoms, temperature intolerance, chest tightness, nervousness, malaise, increased lactate dehydrogenase in the blood, weight loss, dysmenorrhea, bleeding from the uterus, psychotic disorders. Rare: pericardial effusion, thrombotic thrombophlebitis, hypoproterombinemia, increased tension, blindness, neuromuscular deafness, acute respiratory distress syndrome, gastrointestinal hypertension, pancreatic pseudocyst, toxic epidermal necrolysis, hirsutism, thirst, fall, tightness in the chest , reduced motility, ulceration, hepatic artery thrombosis, embolism of hepatic veins. Very rare: abnormal ECG, muscle fatigue, impaired hearing, nephropathy, bleeding cystitis, Stevens-Johnson syndrome, increased fat, liver failure, biliary obstruction. 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. 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.

Treatment with the preparation requires careful monitoring by appropriately trained and equipped staff. 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. If clinical rejection symptoms occur, a change in immunosuppressive therapy should be considered. In general, you can start by administering the drug orally. In the initial postoperative period, the preparation is routinely administered with other immunosuppressive drugs. The concentrate should be used for intravenous infusion only after prior dilution in a 5% Glucose solution or 0.9% NaCl solution. The concentration of the reconstituted solution should be between 0.004 mg / ml and 0.1 mg / ml. The total volume of solution administered as an intravenous infusion over 24 hours is 20 to 500 ml. The solution should be prepared in glass vessels or polyethylene vessels. The syringes, infusion sets and other equipment used to prepare and administer the preparation should not contain PVC. As soon as possible, the drug should be changed from intravenous to oral. Intravenous therapy should not last longer than 7 days.
Liver transplantation. Prophylaxis of transplant rejection in adults: 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 oral dosing, intravenous administration at a dose of 0.01-0.05 mg / kg / day should be initiated as a continuous infusion lasting 24 hours.Prophylaxis of transplant rejection in children: if the patient's clinical status does not permit oral dosing, the initial dose of 0.05 mg / kg / day should be administered as a continuous intravenous infusion over 24 hours.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 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.In the event of a change to the use of tacrolimus, treatment should begin with the oral initial dose recommended in primary immunosuppression.Kidney transplantation. Prophylaxis of transplant rejection in adults: administration of the drug 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 administration should be initiated at a dose of 0.05-0.1 mg / kg / day in a continuous infusion lasting 24 hours.Prophylaxis of transplant rejection in children: if the patient's clinical status does not permit oral dosing, the initial dose of 0.075-0.1 mg / kg / day should be administered as a continuous intravenous infusion over 24 hours.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. In the event of a change to the use of tacrolimus, treatment should begin with the oral initial dose recommended in primary immunosuppression.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. Following antibody induction, oral administration of tacrolimus should be initiated. 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 as a continuous infusion lasting 24 hours should be initiated. Another dosing regimen based on the administration of tacrolimus has also been published. orally within 12 hours of transplantation - this scheme was used in patients who did not show organ failure (eg renal failure).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 by continuous infusion over 24 hours until tacrolimus is reached in whole 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 started 8-12 h after discontinuing the infusion. After antibody induction, oral administration is initiated.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 patients who have changed to the use of tacrolimus, the preparation should be administered orally.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. No dose adjustment is necessary in patients with renal impairment or in the elderly. Children are generally given doses 1.5-2 higher than those used in adults to achieve similar concentrations in the blood. Change in the use of ciclosporin: caution should be exercised when switching from ciclosporin-based therapy to tacrolimus-based therapy. 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.
Dosage should be adjusted primarily based on individual clinical evaluation of rejection and tolerance of transplantation in individual patients. 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 blood levels of tacrolimus should be monitored during the organ transplant period. When administered orally, the lowest blood concentrations should be determined approximately 12 hours 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 after adjusting the dose, introducing changes in immunosuppressive therapy, and concomitantly administering compounds 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 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 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 kidney and heart 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.