Prograf® [Tacrolimus]

Pharmacological properties

at the molecular level, the effects of tacrolimus are determined by binding to the cytosolic protein (fkbp12), which is responsible for the intracellular cumulation of the drug. the fkbp12-tacrolimus complex specifically and competitively binds and inhibits calcineurin, which leads to a calcium-dependent inhibition of t-cell signal transduction pathways, thus preventing the transcription of a discrete group of lymphokine genes.

Tacrolimus is a highly active immunosuppressive substance that inhibits the formation of cytotoxic lymphocytes, which are mainly responsible for transplant rejection, reduce T-cell activation, T-helper-dependent proliferation of B-cells, and the formation of lymphokines (such as interleukins-2, -3 and γ-interferon), expression of the interleukin-2 receptor.

Pharmacokinetics Absorption. Tacrolimus capsules are absorbed in the digestive tract.

WITH_max tacrolimus reaches a peak (T_max) after about 1-3 hours. In some patients, the drug is absorbed over a long period, reaching a relatively uniform absorption profile.

The bioavailability of tacrolimus when administered orally is an average of 20–25%.

After oral administration (0.3 mg / kg / day) of the drug in patients with liver transplant in most patients, equilibrium concentrations were reached for 3 days.

In healthy volunteers, it was shown that the preparations Prograf 0.5 mg, Prograf 1 mg and Prograf 5 mg are bioequivalent when used in equivalent doses.

The rate and degree of absorption of tacrolimus is higher when taking the drug on an empty stomach. With simultaneous use with food, the rate and degree of absorption of tacrolimus decreased, which is most pronounced after eating a meal with a high fat content. The effect of foods high in carbohydrates is less pronounced.

In patients with a stable liver transplant, the bioavailability of Prograf was reduced with oral administration of the drug after eating food with a moderate fat content. There was also a decrease in AUC (27%), C_max (50%) and increase in T_max (173%) in undiluted blood. In a study of patients with stable kidney transplant after oral administration of Prograf, immediately after a standard light breakfast, the effect on bioavailability is less pronounced. There was a decrease in AUC (2-12%), a decrease in C_max (15–38%) and increase in t_max (38–80%) in undiluted blood.

Bile secretion does not affect the absorption of Prograf.

There is a significant correlation between AUC and the minimum levels of the drug in undiluted blood when an equilibrium is reached, and therefore monitoring the minimum levels of the drug in undiluted blood can help in an adequate assessment of the systemic effect of the drug.

Distribution. The nature of the distribution of tacrolimus after iv administration can be described as biphasic. In the systemic circulation, tacrolimus is largely associated with red blood cells. The ratio of undiluted blood / plasma concentration is 20: 1. In plasma, the drug is largely associated with proteins (98.8%), mainly with serum albumin and α₁-acid glycoprotein.

Tacrolimus is widely distributed in the body. The equilibrium volume of distribution (based on plasma concentration) is 1300 L (healthy volunteers). The corresponding indicator based on undiluted blood is 47.6 liters.

Tacrolimus is a substance with a low level of clearance. In healthy volunteers, the average value of the total clearance, which is estimated by the concentration of the drug in undiluted blood, is 2.25 l / h. In adult patients with a liver and kidney transplant, the value of this parameter is 4.1 and 6.7 l / h, respectively. In children with liver transplant, the values ​​of total clearance are 2 times higher than in adult patients with liver transplant.

Factors leading to increased clearance should be taken into account: a low level of hematocrit and protein (leading to an increase in the level of an unbound fraction of tacrolimus) or an increase in metabolism due to corticosteroids.

T_½ tacrolimus is long and variable. In healthy volunteers, the average value of T_½ from undiluted blood - 43 hours. In adult patients and children with liver transplant T_½ averages 11.7 and 12.4 hours, respectively, compared with 15.6 hours in adult kidney transplant patients.

In patients with transplant, an increase in clearance of the drug leads to a decrease in T_½.

Metabolism. Tacrolimus is metabolized in the liver by cytochrome P450 3A4. To a large extent - in the intestines.

Several metabolites have been identified. When used in vitro, it was found that only one metabolite has important immunosuppressive activity. Others have little or no activity. In the systemic circulation, only one metabolite in low concentration is detected. Thus, metabolites do not affect the pharmacological activity of tacrolimus.

Elimination. Following oral administration of tacrolimus labeled ¹⁴With an isotope, most of the radiolabeled drug was excreted in the feces. About 2% - with urine. Less than 1% of unchanged tacrolimus was noted in urine and feces. This indicates that tacrolimus is almost completely metabolized before elimination. The main route of elimination is bile.

Concentrate for the preparation of a solution for iv administration

Distribution. The nature of the distribution of tacrolimus after iv administration can be described as biphasic.

In the systemic circulation, tacrolimus is largely associated with red blood cells. The ratio of the distribution in undiluted blood / plasma concentrations is approximately 20: 1. In plasma, the drug is largely associated with proteins (98.8%), mainly with serum albumin and α₁-acid glycoprotein.

Tacrolimus is widely distributed in the body. The equilibrium volume of distribution based on plasma concentrations is approximately 1300 L (healthy volunteers). The corresponding indicator based on undiluted blood averages 47.6 liters.

Tacrolimus is a drug with low clearance. In healthy volunteers, the average value of the total clearance, which is estimated by the concentration of the drug in undiluted blood, is 2.25 l / h. In adult patients with a liver and kidney transplant, the value of this parameter reaches 4.1 and 6.7 l / h, respectively. In adults with a liver transplant, the value of the total clearance is approximately 2 times higher than in adult patients with a liver transplant.

T_½ tacrolimus is long lasting. In healthy volunteers, the average value of T_½ of undiluted blood is approximately 43 hours. In adult patients and children with liver transplant T_½ averages 11.7 and 12.4 hours, respectively, compared to 15.6 hours in adult kidney transplant patients.

Metabolism. When using in vitro models, 8 metabolites were identified, among which only one has significant immunosuppressive activity.

Tacrolimus is largely metabolized by the hepatic microsomal cytochrome CYP 3A4.

After the introduction of tacrolimus indicated ¹⁴With an isotope, most of the radiolabeled drug was excreted in the feces. About 2% - with urine. Less than 1% of unchanged tacrolimus is detected in urine and feces, which indicates that tacrolimus is almost completely metabolized before elimination. The main route of elimination is bile.

Indications

Capsules

• prevention of rejection during allotransplantation of the kidney, liver and heart;
• treatment of rejection of an allograft resistant to treatment with other immunosuppressive drugs.

Concentrate for the preparation of a solution for iv administration

Prevention and treatment of allograft rejection of the liver, kidneys and heart.

Treatment of rejection of an allograft resistant to other immunosuppressive therapy regimens.

Application

Capsules Prograf drug therapy requires close monitoring by suitably qualified personnel with the appropriate equipment. only physicians with experience in conducting immunosuppressive therapy in patients with transplanted organs can prescribe and change this drug in the course of immunosuppressive therapy.

An accidental, unintended, or uncontrolled replacement of a dosage form with immediate or prolonged release of tacrolimus is dangerous. This can lead to transplant rejection or an increase in the incidence of adverse reactions, including insufficient or excessive immunosuppression, due to clinically significant differences in the systemic effects of tacrolimus. Patients should follow the regimen for the use of a single dosage form of tacrolimus with an appropriate daily dosing schedule; however, a change in the dosage form or regimen should occur only under the supervision of a transplant specialist (see SPECIAL INSTRUCTIONS, Side Effects). After transferring to any other alternative dosage form, it is necessary to control the concentration of tacrolimus in the blood and carry out dose adjustment to maintain a systemic exposure of tacrolimus at an adequate level.

general information

The dose of Prograf should be determined primarily on the basis of a clinical assessment of the risk of rejection and individual tolerance of the drug, taking into account monitoring data on the level of tacrolimus in the blood (see recommendations for determining the minimum concentration in the blood). If clinical symptoms of rejection appear, consideration should be given to the need for correction of the immunosuppressive therapy regimen.

The drug Prograf can be used iv and orally, the dosage can be started with oral administration. In general, you can start with oral administration, if necessary, the contents of the capsules should be dissolved in water and injected through a nasogastric tube.

In the initial postoperative period, Prograf should usually be used simultaneously with other immunosuppressive drugs. The dose of Prograf can be changed depending on the chosen immunosuppressive therapy.

Mode of application

It is recommended to distribute the daily oral dose into 2 doses (morning and evening). Capsules should be taken immediately after removing them from the blister pack. Capsules are swallowed with a liquid (preferably water). To achieve maximum absorption, the drug must be taken on an empty stomach or at least 1 hour before or 2-3 hours after a meal.

To prevent transplant rejection, the state of immunosuppression must be constantly maintained; therefore, the duration of therapy is limited.

Liver transplantation

Prevention of transplant rejection. Adults Oral therapy with Prograf begins at a dose of 0.1-0.2 mg / kg body weight 2 times a day (morning and evening). The use of the drug should begin 12 hours after the completion of the operation. If the patient’s condition does not allow the drug to be taken orally, i.v. is infused for 24 hours at a dose of 0.01-0.05 mg / kg / day.

Prevention of transplant rejection. Children. The initial dose of the drug for oral administration of 0.3 mg / kg of body weight per day is divided into 2 doses (morning and evening). If the clinical condition of the patient does not allow the drug to be taken orally, administer infusion over a period of 24 hours at a dose of 0.05 mg / kg / day.

Maintenance therapy Adults and children. During maintenance therapy, the dose of Prograf is reduced.In some cases, concomitant immunosuppressive therapy drugs are canceled, leaving Prograf as monotherapy. Improving the patients condition after transplantation can change the pharmacokinetics of tacrolimus, so there is a need for dose adjustment.

Rejection treatment. Adults and children. For the treatment of rejection, higher doses of Prograph are used together with additional GCS therapy and short courses of administration of mono- or polyclonal antibodies. If signs of toxicity are detected (see ADVERSE EFFECTS), it may be necessary to reduce the dose of Prograf. When transferring patients to Prograf therapy, the same initial doses are recommended as for primary immunosuppression. When transferring patients with cyclosporine therapy to Prograph, see Special Populations, Conversion (transition) from cyclosporine to tacrolimus.

Kidney transplant

Prevention of transplant rejection. Adults Oral therapy with Prograf begins at a dose of 0.2-0.3 mg / kg body weight 2 times a day (morning and evening). The use of the drug should begin within 24 hours after completion of the operation. If the patient’s condition does not allow the drug to be taken orally, intravenously infused for 24 hours at a dose of 0.05-0.1 mg / kg / day.

Prevention of transplant rejection. Children. The initial dose of the drug for oral administration of 0.3 mg / kg of body weight per day is divided into 2 doses (morning and evening). If the clinical condition of the patient does not allow the drug to be taken orally, infuse for 24 hours at a dose of 0.075-0.1 mg / kg / day.

Maintenance therapy Adults and children. During maintenance therapy, the dose of Prograf is reduced. In some cases, concomitant immunosuppressive therapy drugs are canceled, leaving Prograf as monotherapy. Improving the patients condition after transplantation can change the pharmacokinetics of tacrolimus, so there is a need for dose adjustment.

Rejection treatment. Adults and children. For the treatment of rejection, higher doses of Prograph are used together with additional GCS therapy and short courses of administration of mono- or polyclonal antibodies. If signs of toxicity are detected (see ADVERSE EFFECTS), it may be necessary to reduce the dose of Prograf. When transferring patients to Prograf therapy, the same initial doses are recommended as for primary immunosuppression. When transferring patients with cyclosporine therapy to Prograph, see Special Populations, Conversion (transition) from cyclosporine to tacrolimus.

Heart transplantation

Prevention of transplant rejection. Adults The drug Prograf can be used simultaneously with the induction of antibodies (taking into account the delayed initiation of Prograf therapy) or without prescribing antibodies in a clinically stable condition of patients. After induction with antibodies, oral therapy with Prograf begins with a dose of 0.075 mg / kg / day, distributing it in 2 doses (morning and evening). The use of the drug should begin within 5 days after the completion of the operation, as soon as the clinical condition of the patient is stabilized. If the patient’s condition does not allow the drug to be taken orally, i.v. is infused for 24 hours at a dose of 0.01-0.02 mg / kg / day.

There is an alternative approach in which oral administration of tacrolimus begins within 12 hours after transplantation. This approach is intended for patients without signs of impaired function of the internal organs (kidneys). In this case, tacrolimus in an initial dose of 2-4 mg / day is combined with mycophenolate mofetil and GCS or sirolimus and GCS.

Prevention of transplant rejection. Children. After heart transplantation in children, primary immunosuppression by Prograf can be carried out both in combination with antibody induction and independently.

In cases when antibody induction is not carried out, Prograf is administered as an iv infusion over a period of 24 hours at a dose of 0.03-0.05 mg / kg / day until a concentration of tacrolimus in undiluted blood reaches 15-25 ng / ml. At the first clinical opportunity, it is necessary to transfer the patient to oral administration of the drug in an initial dose of 0.3 mg / kg / day, which is prescribed 8-12 hours after the end of the iv infusion.

After induction with antibodies, oral therapy with Prograf begins with a dose of 0.1-0.3 mg / kg / day, distributing it in 2 doses (morning and evening).

Maintenance therapy Adults and children. With maintenance therapy, the dose of Prograf is reduced. Improving the patients condition after transplantation can change the pharmacokinetics of tacrolimus, so there is a need for dose adjustment.

Rejection treatment. Adults and children. For the treatment of rejection, it is necessary to use higher doses of Prograph together with additional GCS therapy and short courses of administration of mono- or polyclonal antibodies. When adult patients are transferred to Prograf therapy, the initial dose of the drug 0.15 mg / kg / day is divided into 2 doses (morning and evening). When children are transferred to Prograf therapy, the initial dose of the drug 0.2–0.3 mg / kg / day is also divided into 2 doses (morning and evening).

For the transfer of patients with cyclosporine therapy to Prograf, see SPECIAL INSTRUCTIONS.

Rejection treatment - transplantation of other organs

Recommended doses for transplantation of the lungs, pancreas, and intestines are based on limited data from prospective clinical studies. Treatment of patients with lung transplantation with Prograf should be started with a dose of 0.1-0.15 mg / kg / day, patients with pancreatic transplantation should start with a dose of 0.2 mg / kg / day, and with pancreatic transplantation, treatment begins with a dose of 0 3 mg / kg / day.

Special populations

Liver failure. In patients with severely impaired liver function, a dose reduction of tacrolimus may be required to maintain a minimum blood tacrolimus level within the recommended therapeutic range.

Renal failure. Since renal function does not affect the pharmacokinetics of tacrolimus, there is no need for dose adjustment. However, due to the nephrotoxic potential of tacrolimus, it is recommended that careful monitoring of renal function be performed (including plasma creatinine concentrations, calculation of creatinine clearance, and monitoring of urine output).

Elderly patients. There is no information that elderly patients need special doses.

Conversion (transition) from cyclosporine to tacrolimus. Caution should be exercised when transferring patients with basic cyclosporine therapy to drugs with basic tacrolimus therapy (see SPECIAL INSTRUCTIONS and INTERACTIONS). Drug therapy Prograph should be started after determining the concentration of cyclosporin in the blood plasma and analyzing the clinical condition of the patient. Conversion should be postponed in the presence of elevated plasma levels of cyclosporine. In practice, therapy with Prograf begins 12-24 hours after discontinuation of cyclosporine. After the transition, it is recommended to control the level of cyclosporin in the blood, since it is possible to influence the cyclosporin clearance in blood plasma.

Recommendations for achieving the required level of drug concentration in undiluted blood. The choice of the dose of the drug should be based on the results of a clinical evaluation of the process of rejection and tolerance of the drug by each patient individually.

In order to optimize the dose, the concentration of tacrolimus in undiluted blood is determined using immune methods, including semi-automatic enzyme-linked immunosorbent assay on microparticles (MIFA).Comparison of the data on the concentration of tacrolimus in the blood published in the literature with individual clinical indicators is carried out with caution and on the basis of knowledge and understanding of the evaluation method that was used. In modern medical practice, immune methods are used to determine the concentration of tacrolimus in undiluted blood.

In the early period after surgery, minimum levels of tacrolimus in undiluted blood should be monitored. When taken orally, the minimum levels of tacrolimus in undiluted blood should be monitored every 12 hours immediately before the next dose. The frequency of monitoring the level of the drug in the blood should depend on the clinical needs. Since Prograf is a drug with a low clearance level, adjusting the dosage regimen may take several days until the time when changes in blood levels of the drug become apparent. Minimum levels of the drug in the blood should be monitored approximately 2 times a week during the early post-transplant period, and then periodically during maintenance therapy. It is also necessary to control the minimum levels of tacrolimus in the blood after changing the dose of the drug, immunosuppressive regimen, or after simultaneous use with drugs that can affect the concentration of tacrolimus in undiluted blood (see INTERACTIONS).

The results of clinical studies suggest that it is possible to successfully treat most patients if the minimum levels of tacrolimus in the blood are maintained below 20 ng / ml. Interpreting data on the concentration of the drug in undiluted blood, it is important to assess the clinical condition of the patient.

In clinical practice, during the early period after transplantation, the minimum levels of the drug in undiluted blood usually ranged between 5–20 ng / ml after liver transplantation and 10–20 ng / ml after kidney and heart transplantation. In the future, with maintenance therapy after transplantation of the liver, kidneys and heart, the concentration of the drug in the blood varies from 5 to 15 ng / ml.

Concentrate for the preparation of a solution for iv administration. Treatment with Prograf requires careful monitoring, which is carried out by highly qualified personnel and with the help of appropriate equipment. Only a doctor with experience in conducting immunosuppressive therapy in patients with transplanted organs can prescribe this drug and make changes to immunosuppressive therapy.

The drug is administered parenterally if the patients condition does not allow capsules to be taken. As soon as the clinical condition of the patient improves, he is transferred to oral administration of the drug in the form of Prograf capsules.

The duration of iv therapy should not exceed 7 days.

After transferring the patient from parenteral to oral administration in the form of tacrolimus capsules, it should be borne in mind that errors in the use of tacrolimus preparations were noted in practice. An accidental, unintentional or uncontrolled transfer of a patient from one oral dosage form of tacrolimus (standard or prolonged action) to another is dangerous. This can lead to transplant rejection or an increase in the incidence of side effects, including insufficient or excessive immunosuppression due to the corresponding clinical differences in systemic exposure to tacrolimus. The patient needs to be prescribed tacrolimus in the form of a single dosage form with the appropriate daily dosage regimen; changing the dosage form or regimen is possible only under the condition of a thorough examination by a transplant specialist. For the subsequent transition to any other alternative dosage forms, it is necessary to monitor the effect of the drug and dose adjustment to comply with the systemic exposure to tacrolimus.

General information. Recommended doses at the initial stage of treatment are presented below as recommendations. Dosage of the drug Prograf should be based mainly on the clinical assessment of the risk of rejection and individual tolerance of the drug in each patient, as well as on monitoring data on the concentration of tacrolimus in the blood (see SPECIAL INSTRUCTIONS, recommendations for achieving the required level of drug concentration in undiluted blood).

When clinical indicators of rejection appear, it is worth considering the possibility of correcting the immunosuppressive therapy regimen.

Prograf should be used parenterally or orally. In general, the dosage can be started orally, if necessary, by applying the contents of the capsule, dissolved in water, through a nasogastric tube.

Prograf, as a rule, is used in combination with other immunosuppressive drugs at the initial postoperative stage. Dosage of the drug Prograf may vary depending on the selected immunosuppressive regimen.

Prograf concentrate for the preparation of a solution for iv administration is used only iv. Do not administer the drug undiluted. Before use, it is necessary to dilute 5% r-rum of glucose or 0.9% r-rum of sodium chloride in glass, polyethylene or polypropylene vessels. Use only clear and colorless solutions.

Not recommended jet administration of the drug!

The concentration of the solution for infusion should vary between 0.004-0.1 mg / ml. The total infusion over 24 hours should range from 20-500 ml.

Unused concentrate for infusion in an open ampoule or unused reconstituted solution must be discarded immediately to avoid contamination (contamination).

Liver transplantation

Prevention of transplant rejection. Adults The use of the drug should begin about 12 hours after the completion of the operation.

If the patient’s condition does not allow the drug to be taken orally (Prograph capsules), therapy is carried out starting from a dose of 0.01-0.05 mg / kg / day, by administering the drug in the form of an iv infusion for 24 hours.

Prevention of transplant rejection. Children. If the patient’s condition does not allow the drug to be taken orally (capsule Prograph), therapy is carried out starting with a dose of 0.05 mg / kg / day as an intravenous infusion over a period of 24 hours

Maintenance therapy Adults and children. During maintenance therapy, the dose of Prograf is usually reduced. In some cases, drugs of concomitant immunosuppressive therapy can be discontinued using Prograf as monotherapy. Improving the patients condition after transplantation can change the pharmacokinetics of tacrolimus, so there is a need for dose adjustment.

Rejection treatment. Adults and children. For the treatment of rejection, it is necessary to use the drug Prograf at higher doses, together with additional GCS therapy and short courses of administration of mono- / polyclonal antibodies. If signs of toxicity occur, a reduction in the dose of Prograf is possible.

When transferring patients to Prograf therapy, the same initial doses are recommended as for the prevention of immunosuppression. When transferring patients with cyclosporine therapy to Prograph, see SPECIAL INSTRUCTIONS, dose adjustment in special patient groups, Transition from cyclosporine therapy.

Kidney transplant

Prevention of transplant rejection. Adults Therapy should be started within 24 hours after completion of the operation.

If the patient’s condition does not allow the drug to be taken orally (Prograph capsules), IV therapy should be started with a dose of 0.05–0.1 mg / kg / day, administering the drug as an IV infusion for 24 hours.

Prevention of transplant rejection. Children.If the patient’s condition does not allow the drug to be taken orally (capsule Prograph), IV therapy should be started with a dose of 0.075-0.1 mg / kg / day, by administering the drug as an IV infusion over 24 hours.

Maintenance therapy Adults and children. During maintenance therapy, the doses of Prograf are reduced. In some cases, concomitant immunosuppressive therapy drugs may be discontinued, leaving Prograph as a basic component of dual therapy. Improving the patients condition after transplantation can change the pharmacokinetics of tacrolimus, so there is a need for dose adjustment.

Treatment of rejection reactions. Adults and children. For the treatment of rejection, it is necessary to use the drug Prograf at higher doses, together with additional GCS therapy and short courses of administration of mono- / polyclonal antibodies. If signs of toxicity occur, a reduction in the dose of Prograf is possible.

When transferring patients to Prograf therapy, the same initial doses are recommended as for the prevention of immunosuppression. When transferring patients with cyclosporine therapy to Prograph, see SPECIAL INSTRUCTIONS, dose adjustment in special patient groups, Transition from cyclosporine therapy.

Heart transplantation

Prevention of transplant rejection. Adults Prograf should be used together with antibody induction (taking into account the delayed initiation of therapy with Prograf). After antibody induction, the drug should be started within 5 days after the operation is completed, as soon as the patients clinical condition is stabilized. If the patient’s condition does not allow the drug to be taken orally (capsule Prograph), it is necessary to carry out iv therapy, starting with a dose of 0.01-0.02 mg / kg / day, administering the medicine as an infusion for 24 hours

Prevention of transplant rejection. Children. After heart transplantation in children, primary immunosuppression with Prograf can be carried out both with antibody induction and independently.

In cases when antibody induction is not carried out, Prograf should be administered iv in an initial dose of 0.03–0.05 mg / kg / day, administering the drug as an infusion for 24 hours until the concentration of tacrolimus in undiluted blood reaches 15– 25 ng / ml. At the first clinical opportunity, it is necessary to transfer the patient to an oral administration of the drug (Prograph capsules) at an initial dose of 0.30 mg / kg / day, which is prescribed 8-12 hours after the end of the infusion.

Maintenance therapy Adults and children. During maintenance therapy, the doses of Prograf are reduced. Improving the patients condition after transplantation can change the pharmacokinetics of tacrolimus, so there is a need for dose adjustment.

Rejection treatment. Adults and children. For the treatment of rejection, it is necessary to use the drug Prograf at higher doses, together with additional GCS therapy and short courses of administration of mono- / polyclonal antibodies.

When transferring adult patients to oral therapy with Prograf capsules, the initial dose of the drug is 0.15 mg / kg / day divided into 2 doses (morning and evening).

When transferring children to oral therapy with Prograf capsules, the initial dose of the drug is 0.2-0.3 mg / kg / day divided into 2 doses (morning and evening).

Information on transferring patients with cyclosporine therapy to Prograph is described in the SPECIAL INSTRUCTIONS section, dose adjustment in special patient groups. Transition from cyclosporine therapy.

Contraindications

Hypersensitivity to tacrolimus (or other macrolides) and other inactive ingredients of the drug.

Side effects

Due to the characteristics of the underlying disease and the large number of drugs used simultaneously after transplantation, it is difficult to establish the exact profile of the side effects of immunosuppressants.

Many of the side effects below are reversible and / or dose dependent.In each group, adverse reactions are listed in decreasing order of severity. With oral administration of the drug, there are fewer cases of adverse reactions compared with intravenous administration.

Adverse reactions are classified by organs and systems, are given below depending on the frequency of occurrence: very often (1/10); often (1/100, but 1/10); infrequently (1/1000, but 1/100); rarely (1/10 000, but 1/1000); very rarely (1/10 000), unknown (not enough data to establish the frequency).

From the vessels: very often - AH; often - bleeding, thromboembolic and ischemic complications, impaired peripheral circulation, arterial hypotension; infrequently - a heart attack, deep vein thrombosis of the extremities, shock.

From the side of the heart: often - ischemic coronary disorders, tachycardia; infrequently - ventricular arrhythmia and cardiac arrest, heart failure, cardiomyopathy, ventricular hypertrophy, supraventricular arrhythmia, tachycardia, ECG changes, rhythm disturbance, heart rate and pulse, pericarditis; rarely - pericardial effusion; very rarely - a change in echocardiography.

From the digestive system: very often - diarrhea, nausea; often - inflammatory diseases of the gastrointestinal tract, the occurrence of ulcers and perforation of the gastrointestinal tract, gastrointestinal bleeding, stomatitis and ulceration of the oral mucosa, ascites, vomiting, abdominal pain, dys