Tacrolimus - instructions for use, dose, side effects, contraindications

Component name	Capsules 0.5 mg	Capsules 1.0 mg	Capsules 5.0 mg
*Active substance:*
Tacrolimus monohydrate, in terms of tacrolimus	0.511 mg 0.5 mg	1.022 mg 1.0 mg	5,110 mg 5.0 mg
*Excipients:*
Lactose monohydrate (milk sugar)	224.412 mg	223.401 mg	215.313 mg
Croscarmellose sodium	0.5 mg	1.0 mg	5.0 mg
Giprolase	2.277 mg	2.277 mg	2.277 mg
Magnesium stearate	2.3 mg	2.3 mg	2.3 mg
Capsule body composition:
Dye sunset sunset yellow			0,14%
Titanium dioxide	2,0%	2,0%	2,0%
Gelatin	up to 100%	up to 100%	up to 100%
Composition of cap capsule:
Iron Oxide Dye Oxide			0,1890%
Indigocarmine	0,0367%	0,0905%
Titanium dioxide	1,5605%	2,0%	1,2198%
Gelatin	up to 100%	up to 100%	up to 100%

Description:

Dosage of 0.5 mg. Capsules hard gelatinous № 2. The case of white color, a cap of blue color opaque.

Dosage of 1.0 mg. Capsules firm gelatinous № 2. The case of white color, a cover of dark blue color opaque.

Dosage of 5.0 mg. Capsules hard gelatinous № 2. The case of orange color, a cover of gray color opaque.

Contents of capsules: a mixture of powder and granules of white or almost white color. It is possible to compact the contents of the capsules into lumps in the shape of a capsule, which are easily disintegrated when pressed.

Pharmacotherapeutic group:immunosuppressive agent - calcineurin inhibitor

Pharmacodynamics:

At the molecular level, effects and intracellular cumulation of tacrolimus are due to binding to the cytosolic protein (FKBP 12). Complex FKBP 12-tacrolimus specifically and competitively inhibits calcineurin by providing calcium-dependent blocking of T-cell signaling pathways and preventing transcription of a discrete series of lymphokine genes.

Tacrolimus is a highly active immunosuppressant. In experiments in vitro and in vivo tacrolimus clearly reduced the formation of cytotoxic lymphocytes, which play a key role in the transplant rejection reaction. Tacrolimus inhibits the formation of cytotoxic lymphocytes, which are mainly responsible for graft rejection, reduces T-cell activation, T-helper dependent B-cell proliferation, and the formation of lymphokines (interleukin -2, -3, γ-interferon), receptor expression interleukin-2.

Pharmacokinetics:

Absorption

Tacrolimus is absorbed from the gastrointestinal tract (GIT); the main place of absorption is the upper gastrointestinal tract.

When administered orally, the median time to reach the maximum concentration (TC_m_Oh) tacrolimus in the blood is 1-3 hours. Have some patients tacrolimus absorbed over a long period, reaching a relatively flat absorption profile. Bioavailability when taking the drug inside is on average 20-25%. After oral administration (0.3 mg / kg / day) of the drug in patients with liver transplant in most patients, equilibrium concentrations of tacrolimus were achieved within 3 days.

The highest rate and degree of absorption of tacrolimus is achieved when taking the drug on an empty stomach. The speed and extent of absorption of tacrolimus while taking with food are reduced, especially in the case of high levels of fat in the diet. The influence of foods rich in carbohydrates on the absorption of tacrolimus is less pronounced. In stable patients after liver transplantation, bioavailability decreased with simultaneous intake of capsules with food with moderate fat content. There was also a decrease in the area under the pharmacokinetic curve "concentration-time" (AUC) (27%), maximum concentration (FROM_m_Oh) (50%) and increase TS_m_Oh (173%) in whole blood.

In stable patients after kidney transplantation, when taking the drug immediately after a standard breakfast, the effect of food on the bioavailability of tacrolimus was less pronounced. There was a decrease AUC (by 2-12%) and FROM_m_Oh (by 15-38%), and an increase TS_m_Oh (by 38-80%).

Isolation of bile does not affect the absorption of tacrolimus.

On the background of drug therapy, when an equilibrium state is reached, a high correlation is observed between AUC and minimum concentrations of tacrolimus in whole blood. Therefore, monitoring the minimum concentrations of tacrolimus in whole blood can serve as a method that provides an adequate assessment of the systemic exposure of tacrolimus.

Distribution

The distribution of tacrolimus after intravenous administration of the drug to humans is biphasic.

In the systemic circulation tacrolimus largely associated with erythrocytes. The ratio of tacrolimus concentrations in whole blood and plasma is approximately 20: 1. In the blood plasma tacrolimus is largely bound (> 98.8%) with proteins, mainly with serum albumin and α-1-acid glycoprotein.

Tacrolimus is widely distributed in the body. The equilibrium volume of distribution based on plasma concentrations is approximately 1300 liters (healthy volunteers). The same index, calculated on whole blood, is on average 47.6 liters.

Tacrolimus is a drug with a low level of clearance. In healthy volunteersthe average value of the total clearance, estimated by the concentration of tacrolimus in whole blood, is 2.25 l / h. In adult patients with graft, kidney and heart, the values of this parameter were 4.1 l / h, 6.7 l / h and 3.9 l / h, respectively. In children with liver transplant, the total clearance value is approximately 2 times higher than in adult patients with a liver transplant. Low hematocrit and hypoproteinemia contribute to an increase in the unbound fraction of tacrolimus, accelerating the clearance of tacrolimus.

The half-life (T_1/2) tacrolimus is long and variable. In healthy volunteers, the mean T_1/2of whole blood is approximately 43 hours. In adults and children with liver transplant T_1/2 an average of 11.7 hours and 12.4 hours, respectively, compared with 15.6 hours in adult patients with a kidney transplant.

Metabolism

Tacrolimus is actively metabolized in the liver, mainly by isoenzyme CYP3A4. Metabolism tacrolimus intensively flows in the intestinal wall. Several metabolites of tacrolimus have been identified. In experiments in vitro it was shown that only one of the metabolites has immunosuppressive activity close to that of tacrolimus. Other metabolites were characterized by weak immunosuppressive activity or lack of it. In the systemic circulation, only one of the metabolites of tacrolimus in low concentrations was detected. Thus, the pharmacological activity is practically independent of metabolites.

Excretion

After taking tacrolimus labeled ¹⁴With the isotope, the majority of the radiolabeled drug was excreted by the intestine. About 2% is excreted by the kidneys, while about 1% of tacrolimus was determined unchanged. Consequently, tacrolimus before elimination almost completely metabolized, the main way of elimination was bile.

Indications:

Prevention of rejection of the liver, kidney or heart allograft.

Treatment of allograft rejection reaction, resistant to other regimens of immunosuppressive therapy.

Contraindications:

Hypersensitivity to tacrolimus, auxiliary components of the drug, macrolides.

Deficiency of lactase, intolerance lactose, glucose-galactose malabsorption.

Pregnancy and lactation:

Pregnancy

The results of studies involving people show that the drug can penetrate the placenta. Some data on the application of tacrolimus in transplanted patients suggest that there is no higher risk of adverse effects of the drug on the course and outcome of pregnancy compared to other immunosuppressants.

There are reports of spontaneous abortions. There are no other epidemiological data on this issue. Since the safety of tacrolimus in pregnant women is not sufficiently established, the drug is taken during pregnancy only in the absence of a safer alternative and only in those cases where the benefits of treatment justify the potential risk to the fetus.

In order to identify potential unwanted reactions tacrolimus is recommended to monitor the condition of newborns whose mothers during pregnancy were taking tacrolimus (in particular, pay attention to the kidney function).

In rats and rabbits tacrolimus had embryotoxic and fetotoxic effects in doses that were toxic to the mother's body.When toxic doses of tacrolimus were used in female rats, reproduction was impaired, including childbirth, and in offspring, weight loss at birth, decreased viability, and stunted growth.

Breastfeeding period

According to clinical experience, tacrolimus penetrates into breast milk. Since it is not possible to exclude the adverse effects of tacrolimus on the newborn, women who take the drug should refrain from breastfeeding.

Fertility

Pre-clinical studies in rats showed a negative effect of tacrolimus on male fertility, which was reflected in a decrease in the number and mobility of spermatozoa.

Dosing and Administration:

Therapy of the drug requires careful monitoring by personnel with the appropriate qualifications and having the necessary equipment at their disposal. Prescribe a drug or make changes in immunosuppressive therapy can only doctors with experience of immunosuppressive therapy in patients with transplanted organs.

The uncontrolled transfer of patients from one drug tacrolimus to another (including the transition from conventional capsules to prolonged capsules) is unsafe.This can lead to rejection of the transplant or an increase in the incidence of side effects, including hypo- or hyperimmunosuppression due to the appearance of clinically significant differences in the exposure of tacrolimus. The patient should take one of the dosage forms of tacrolimus in accordance with the recommended dosage regimen.

The change in dosage form or dosage regimen should be carried out only under the supervision of a specialist in the field of transplantology. After the transfer, it is necessary to carefully monitor the concentration of tacrolimus in the blood and adjust the dose of the drug to maintain the systemic exposure of tacrolimus at an adequate level.

If you miss Tacrolimus capsules, take the next dose in time. A double dose of the drug should not be taken.

The initial doses presented below should only be considered as recommendations. In the initial postoperative period Tacrolimus usually used in combination with other immunosuppressants. The dose may vary depending on the regimen of immunosuppressive therapy.The choice of the dose of the drug should be based, first of all, on the clinical evaluation of the risk of rejection and individual drug tolerance, as well as on the monitoring of tacrolimus concentration in the blood.

When there are clinical signs of rejection, consideration should be given to the need for correcting the regimen of immunosuppressive therapy.

In most cases Tacrolimus in the form of capsules is administered orally. Children up to 3 years of the drug should be taken, after opening the capsule and mixing its contents with water. If necessary, the contents of the capsules can be mixed with water and injected through a nasogastric tube.

The daily dose of the drug is divided into 2 doses (in the morning and in the evening) in equal doses. Capsules should be taken immediately after they are removed from the blister.

Capsules are washed down with a liquid, preferably water. To achieve maximum absorption, capsules should be taken on an empty stomach, 1 hour or 2-3 hours after eating.

To prevent rejection of the graft, the state of immunosuppression must be maintained at all times, hence the duration of therapy is not limited.

Liver transplantation

Prevention of graft rejection

Adults

Oral capsule therapy Tacrolimus it is necessary to start with a dose of 0.10-0.20 mg / kg / day, divided into two doses (for example, in the morning and in the evening). If the patient's condition allows taking the capsules inside, the drug should be started approximately 12 hours after the operation is completed.

If the patient's condition does not allow the medication to be taken orally, intravenous therapy should be started in the form of a solution for infusions at a dose of 0.01-0.05 mg / kg / day as a continuous 24-hour infusion.

Children

The initial dose of 0.30 mg / kg / day of the drug should be divided into two doses (for example, in the morning and in the evening). If the patient's clinical condition does not allow him to take the medicine inside, intravenous therapy should be started in the form of a solution for infusions at a dose of 0.05 mg / kg / day as a continuous 24-hour infusion.

Supportive therapy

Adults and children

In the posttransplant period, the doses of the drug are usually reduced. In some cases, it is possible to cancel preparations of concomitant immunosuppressive therapy, leaving Tacrolimus as a monotherapy.When the patient's condition improves after transplantation, the pharmacokinetics of tacrolimus may change, a dose adjustment may be required.

Treatment of rejection

Adults and children

To treat episodes of rejection, it is necessary to use higher doses of the drug in combination with additional glucocorticosteroid therapy and short courses of mono / polyclonal antibodies. If signs of toxicity are noted, a dose reduction may be required.

When transferring patients to capsule therapy Tacrolimus the same initial doses are recommended, as with primary immunosuppression. Information on the transfer of patients with cyclosporine therapy on Tacrolimus is given at the end of the section "Correction of the dose of the drug in special patient populations."

Kidney Transplantation

Prevention of rejection

Adults

Oral capsule therapy should be started at a dose of 0.20-0.30 mg / kg / day, divided into two divided doses (eg, in the morning and in the evening). The drug should be started within 24 hours after the operation is completed. If the patient's condition does not allow taking the medication internally, intravenous therapy should be started from a dose of 0.05-0.10 mg / kg / day as a continuous 24-hour infusion.

Children

The initial dose of 0.30 mg / kg / day of the drug Tacrolimus should be divided into two doses (for example, in the morning and in the evening). If the patient's clinical condition does not allow him to take the drug inside, intravenous therapy should be started at a dose of 0.075-0.100 mg / kg / day as an intravenous infusion within 24 hours.

Supportive therapy

Adults and children

In the course of maintenance therapy, the doses of the drug are usually reduced. In some cases, it is possible to cancel concomitant immunosuppressants, leaving Tacrolimus as a basic component of dual therapy. If the patient's condition improves after transplantation, the pharmacokinetics of tacrolimus may change, a dose adjustment may be required.

Treatment of rejection reaction

Adults and children

When transferring patients to capsule therapy Tacrolimus the same initial doses are recommended, as with primary immunosuppression.Information on the transfer of patients with cyclosporine therapy on Tacrolimus is given at the end of the section "Correction of the dose of the drug in special patient populations."

Heart transplantation

Prevention of rejection

Adults

Tacrolimus can be used in combination with induction therapy with antibodies (which allows delaying the onset of the drug) or without antibodies clinically stable patients. Following the induction of antibodies, oral capsule therapy should be started at a dose of 0.075 mg / kg / day divided into two doses (eg, morning and evening), within 5 days after surgery, once the patient's clinical condition is stabilized. If the patient's condition does not allow taking the drug inside, it is necessary to start intravenous therapy at a dose of 0.01-0.02 mg / kg / day as a continuous 24-hour infusion.

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 internal organs (eg, kidneys). In this case tacrolimus in an initial dose of 2-4 mg / day is combined with mycophenolate mofetil and glucocorticosteroids, or sirolimus and glucocorticosteroids.

Children

After heart transplantation in children, primary immunosuppression with the drug Tacrolimus can be carried out both in combination with induction by antibodies, and independently. In those cases when induction is not carried out with antibodies and tacrolimus is administered intravenously, the recommended initial dose is 0.03-0.05 mg / kg / day as a continuous 24-hour infusion until the tacrolimus concentration in whole blood reaches 15-25 ng / ml. At the first clinical opportunity, the patient should be transferred to the oral administration of the drug. The initial oral dose should be 0.30 mg / kg / day and administered through 8-12 hours after discontinuation of intravenous infusion.

Following the induction of antibodies, oral capsules should be started at a dose of 0.10-0.30 mg / kg / day, divided into two doses (for example, in the morning and in the evening).

Supportive therapy

Adults and children

In the course of maintenance therapy, the doses of the drug are usually reduced. Improvement of the patient's condition after transplantation can change the pharmacokinetics of tacrolimus, and there will be a need for correction of the dose of the drug.

Treatment of rejection reaction

Adults and children

To treat episodes of rejection, it is necessary to use the drug Tacrolimus in higher doses in combination with additional glucocorticosteroid therapy and short courses of mono / polyclonal antibodies.

When transferring patients to capsule therapy Tacrolimus the initial daily dose for adults is 0.15 mg / kg / day, for children 0.2-0.3 mg / kg / day should be divided into two doses (for example, in the morning and in the evening).

Information on the transfer of patients with cyclosporine therapy Tacrolimus is given at the end of the section "Correction of the dose of the drug in special patient populations."

Recommended doses for treatment of rejection after allotransplantation of other organs

Recommendations for dosing the drug Tacrolimus for patients after lung, pancreas and small intestine allotransplantation are based on data from selected prospective clinical studies.

After transplantation lung Tacrolimus is used in the initial dose of 0.10-0.15 mg / kg / day.

After allotransplantation pancreas the initial dose is 0.20 mg / kg / day.

After allotransplantation small intestine the initial dose of the drug is 0.3 mg / kg / day.

Correction of dose of the drug in special populations of patients

Patients with hepatic insufficiency

Patients with severe hepatic impairment may require a dose reduction in order to maintain the target minimum concentration of the drug within the recommended values.

Patients with renal insufficiency

Since the pharmacokinetics of tacrolimus does not change with renal function, no dose adjustment is required. However, due to the presence of nephrotoxic action in tacrolimus, it is recommended to carefully monitor the kidney function (including serum creatinine concentration, creatinine clearance and diuresis level).

Children

To achieve similar concentrations of the drug in the blood, children usually require doses that are 1.5-2 times higher than doses for adults.

Elderly patients

Currently, there is no evidence of the need to adjust the dose of the drug for elderly patients.

Transfer from cyclosporine to drug treatment Tacrolimus

Simultaneous use of drugs of cyclosporine and tacrolimus may increase the half-life of cyclosporine and enhance toxic effects.Therefore, care must be taken when transferring patients from cyclosporine to tacrolimus therapy. Capsule treatment Tacrolimus should be started after an assessment of the concentrations of cyclosporine in the blood and the clinical state of the patient. Go to Tacrolimus should be postponed in the presence of elevated concentrations of cyclosporine in the patient's blood. Practice shows that Tacrolimus appoint 12-24 hours after the abolition of cyclosporine. After the transfer of the patient, it is necessary to continue monitoring the concentrations of cyclosporine in the patient's blood in connection with the possibility of impaired clearance of cyclosporine.

Recommendations for monitoring the therapeutic concentration of tacrolimus in the blood

Dose choice Tacrolimus is based on clinical assessment of rejection and drug tolerability in each individual patient. To optimize dosing, tacrolimus concentration in whole blood is measured using immune methods, including semi-automatic enzyme-linked immunosorbent assay (MIFA). A comparison of data on the concentration of tacrolimus in the blood, published in the literature,with individual clinical indicators should be conducted with caution and based on knowledge and understanding of the valuation method used.

In the postoperative period, it is important to monitor the minimum concentrations of tacrolimus in whole blood. To determine the minimum concentrations of tacrolimus in the blood, it is necessary to obtain blood samples 12 hours after taking the drug, immediately before the next dose. The frequency of tacrolimus concentration in the blood should depend on clinical needs. As tacrolimus is a drug with a low clearance value, after adjusting the dose, the time to reach the equilibrium minimum concentration of tacrolimus in the blood can be several days. The minimum concentration of tacrolimus in the blood should be monitored approximately twice per week during the early post-transplant period and then periodically during maintenance therapy. The minimum concentration of tacrolimus in the blood should also be monitored after changing the dose of the drug Tacrolimus, the regime of immunosuppression or after joint application with drugs that affect the concentration of tacrolimus in whole blood.

The results of clinical studies indicate that the treatment with capsules Tacrolimus is most successful in those cases when the minimum concentration of tacrolimus in the blood does not exceed 20 ng / ml. Interpreting concensus datatracings of tacrolimus in whole blood, it is important to assess the clinical state of the patient.

In clinical practice, in the early post-transplant period, the minimum concentration of tacrolimus in whole blood usually varies between 5-20 ng / ml after liver transplantation and 10-20 ng / ml after kidney and heart transplantation. Later, during maintenance therapy after liver, kidney and heart transplantation, tacrolimus concentrations in the blood range from 5 to 15 ng / ml.

Side effects:

Many of the adverse events presented below are reversible and / or decreased with a reduced dose.

Undesirable phenomena classified by organs and systems are listed below in order of decreasing detection frequency: Often (≥ 1/10), often (from ≥ 1/100 to <1/10), infrequently (from ≥ 1/1000 to <1/100), rarely (from ≥ 1/10 000 to <1/1 000), rarely (< 1/10 000), frequency unknown (to establish the frequency of which data is not enough).

Heart Disease: often - ischemic diseases of the coronary arteries, tachycardia; infrequent - ventricular arrhythmia and cardiac arrest, heart failure, cardiomyopathy, ventricular hypertrophy, supraventricular arrhythmia, palpitations, abnormalities in ECG parameters, violation of heart rate and rhythm; rarely - exudative pericarditis; very rarely - changes in the echocardiogram, prolongation of the QT interval, disturbance of the rhythm of the heart such as "pirouette" (bidirectional spindle ventricular tachycardia).

Violations of the blood and lymphatic system: often - anemia, leukopenia, thrombocytopenia, leukocytosis, a decrease or increase in hemoglobin and / or hematocrit, deviations in the analysis of erythrocytes; infrequently - coagulopathy, abnormalities in the coagulogram, pancytopenia, neutropenia; rarely - thrombotic thrombocytopenic purpura, hypoprothrombinemia; unknown - partial red cell aplasia, agranulocytosis, hemolytic anemia.

Disturbances from the nervous system: very often - a tremor, a headache; often - convulsions, impaired consciousness, paresthesia and dysesthesia, peripheral neuropathies,dizziness, violation of writing, nervous system disorders; infrequently - coma, hemorrhages in the central nervous system and cerebral circulatory disorders, paralysis and paresis, encephalopathy, speech and articulation disorders, amnesia; rarely - increased muscle tone; very rarely - myasthenia gravis.

Visual impairment: often - blurred vision, photophobia, eye diseases, impaired vision; infrequently - cataract; rarely - blindness.

Hearing disorders and labyrinthine disorders: often - noise (ringing) in the ears; infrequently - hearing loss; rarely - sensorineal deafness; very rarely - hearing impairment.

Disturbances from the respiratory system, chest and mediastinal organs: often shortness of breath, pulmonary parenchymal disorders, pleural effusion, pharyngitis, cough, nasal congestion, rhinitis; infrequent - respiratory failure, respiratory tract disorders, asthma; rarely acute respiratory distress syndrome.

Disorders from the gastrointestinal tract: very often - diarrhea, nausea; often - inflammatory diseases of the gastrointestinal tract, gastrointestinal ulcers and perforations,gastrointestinal hemorrhage, stomatitis and ulceration of the oral mucosa, ascites, vomiting, gastrointestinal and abdominal pain, dyspepsia, constipation, flatulence, bloating and swelling in the abdomen, loose stools, symptoms of gastrointestinal disturbances; infrequent paralytic ileus (paralytic ileus), peritonitis, acute and chronic pancreatitis, increased amylase activity in the blood, gastroesophageal reflux disease, impaired gastric evacuation function; rarely - subileus, pancreatic pseudocysts.

Disturbances from the liver and bile ducts: often - increased activity of "liver" enzymes, pathological changes in functional liver tests, violations of liver function, cholestasis and jaundice, damage to liver cells and hepatitis, cholangitis; rarely - thrombosis of the hepatic artery, obliterating endophlebitis of the hepatic veins; very rarely - liver failure, stenosis of the bile duct.

Disorders from the kidneys and urinary tract: very often - impaired renal function; often - renal failure, acute renal failure, oliguria,acute tubular necrosis, toxic nephropathy, urinary syndrome, disorders of the bladder and urethra; infrequently - anuria, hemolytic uremic syndrome; very rarely - nephropathy, hemorrhagic cystitis.

Disturbances from the skin and subcutaneous tissues: often - itching, rash, alopecia, acne, hyperhidrosis; infrequently - dermatitis, photosensitivity; rarely - toxic epidermal necrolysis (Lyell's syndrome); very rarely - Stevens-Johnson syndrome.

Disturbances from musculoskeletal system and connective tissue: often - arthralgia, muscle cramps, pain in the limbs, back pain; infrequently - compound disorders.

Disorders from the endocrine system: rarely - hirsutism.

Disorders from the metabolism and nutrition: very often - hyperglycemia, diabetes, hyperkalemia; often hypomagnesemia, hypophosphatemia, hypokalemia, hypocalcemia, hyponatremia, hypervolemia, hyperuricemia, decreased appetite, anorexia, metabolic acidosis, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, electrolyte disturbances; infrequently - dehydration, hypoproteinemia, hyperphosphataemia, hypoglycemia.

Immune system disorders: in patients taking tacrolimus, allergic and anaphylactic reactions were observed.

Infectious and parasitic diseases: in patients receiving tacrolimus, as in the treatment of other immunosuppressive drugs, the risk of developing local and generalized infectious diseases (viral, bacterial, fungal, protozoal) is increased. The course of previously diagnosed infectious diseases may worsen.

Cases of VK virus-associated nephropathy, as well as cases of progressive multifocal leukoencephalopathy (PML) associated with JC- a virus, in patients receiving immunosuppressants, including tacrolimus.

Trauma, intoxication and complications of manipulation: often - primary dysfunction of the transplant.

There have been cases of errors in the use of tacrolimus preparations, including unreasonable, unintentional or uncontrolled transfer of patients from one tacrolimus dosage form (standard or prolonged) to another. There are reports that some of these cases have been associated with transplant rejection (it is not possible to estimate the frequency of occurrence according to available data).

Benign, malignant and unidentified neoplasms (including cysts and polyps): patients receiving immunosuppressive therapy have a higher risk of developing malignant neoplasms. When tacrolimus was used, benign as well as malignant tumors were recorded, including the Epstein-Barr virus (EBV) - associated lymphoproliferative neoplasms of the skin.

Vascular disorders: very often - arterial hypertension; often - bleeding, thromboembolism and ischemic disorders, peripheral circulatory disorders, arterial hypotension; infrequently, myocardial infarction, deep vein thrombosis of the extremities, shock.

General disorders and disorders at the site of administration: often - asthenic condition, febrile conditions, swelling, pain and discomfort, increased alkaline phosphatase activity in the blood, increased body weight, impaired body temperature perception; infrequently - multi-organ failure, flu-like syndrome, impaired perception of the temperature of the environment, a feeling of squeezing in the chest, a sense of anxiety, deterioration of well-being,increased lactate dehydrogenase activity in the blood, weight loss; rarely - a feeling of thirst, loss of balance (falling), a feeling of stiffness in the chest, difficulty moving, an ulcer; very rarely - an increase in the mass of adipose tissue.

Violations of the genitals and mammary glands: infrequently - dysmenorrhea and uterine bleeding.

Mental disturbance: very often - insomnia; often - symptoms of anxiety, confusion and disorientation, depression, depressed mood, affective disorders, nightmares, hallucinations, mental disorders; infrequently - psychotic disorders.

Overdose:

Information on overdose is limited. Several episodes of occasional overdoses have been reported in patients taking tacrolimus medications.

Symptoms including tremor, headache, nausea, vomiting, infection, urticaria, lethargic state, increased urea nitrogen concentration in the blood, hypercreatinemia, increased activity of alanine aminotransferase.

Currently there are no antidotes to tacrolimus. In case of an overdose, symptomatic treatment. Given the high molecular weight of tacrolimus, poor solubility in water, and pronounced binding to erythrocytes and plasma proteins, dialysis is ineffective. In individual patients with very high concentrations of tacrolimus in the blood, hemofiltration or diafiltration was effective. Gastric lavage and / or the use of adsorbents (eg, activated carbon) may be effective if these measures are taken shortly after taking the drug.

Interaction:

Metabolic interactions

Tacrolimus, located in the systemic circulation, is metabolized by hepatic cytochrome CYP3A4. When taken orally tacrolimus is also metabolized in the intestinal cytochrome system CYP3A4. Simultaneous reception of drugs or herbs with established inhibitory or inducing action on CYP3A4 can respectively increase or decrease the concentration of tacrolimus in the blood. To maintain adequate and permanent exposure of tacrolimus while simultaneous administration with drugs that can change activity CYP3A4 or have a different effect on the pharmacokinetics of tacrolimus, it is recommended to monitor the concentration of tacrolimus in the blood and, if necessary, adjust the dose or cancel the drug.You should also monitor the interval QT (by electrocardiography), renal function and possible side effects.

Inhibitors of Metabolism

Based on clinical experience, it was found that the concentration of tacrolimus in the blood can significantly increase the following drugs: antifungal agents (ketoconazole, fluconazole, itraconazole, voriconazole), macrolide antibiotics (erythromycin), HIV protease inhibitors (ritonavir, nelfinavir, saquinavir) or hepatitis C virus protease inhibitors (telaprevir, boceprevir). When used simultaneously with these drugs, a reduction in doses of tacrolimus is often required. Less pronounced drug interaction was observed with the simultaneous use of drugs tacrolimus with clotrimazole, clarithromycin, josamycin, nifedipine, nicardipine, diltiazem, verapamil, amiodarone, danazol, ethinyl estradiol, omeprazole and nefazodone.

In studies in vitro it was shown that the following substances are potential inhibitors of tacrolimus metabolism: bromocriptine, cortisone, dapsone, ergotamine, gestodene, lidocaine, mephenytoin, miconazole, midazolam, nilvadipine, norethisterone, quinidine, tamoxifen, troleandomycin.

It is also recommended to avoid grapefruit juice in connection with the possibility of increasing the level of tacrolimus concentration in the blood.

Lansoprazole and ciclosporin can potentially inhibit CYP3A4-mediated metabolism of tacrolimus and increase its concentration in the blood.

Inductors of metabolism

Based on clinical experience, it was found that the concentration of tacrolimus in the blood can significantly reduce the following medicines: rifampicin, phenytoin, St. John's wort. At simultaneous application of These drugs with tacrolimus may require an increase in doses of tacrolimus.

Clinically significant interactions were observed with phenobarbital.

Glucocorticosteroids in maintenance doses usually reduce the concentration of tacrolimus in the blood. Prednisolone or methylprednisolone may increase or decrease the concentration of tacrolimus.

Carbamazepine, metamizol sodium and isoniazid can reduce the concentration of tacrolimus in the blood.

Effect of tacrolimus on the metabolism of other drugs

Tacrolimus inhibits CYP3A4 and with simultaneous admission may affect the drugs metabolized by isoenzyme CYP3A4. The half-life of cyclosporin with simultaneous application with tacrolimus is increased. Synergistic / additive nephrotoxic effects may also occur. For these reasons, simultaneous administration of cyclosporine and tacrolimus is not recommended, and in the appointment of tacrolimus to patients who have previously taken ciclosporin, care must be taken.

Tacrolimus increases the level of phenytoin in the blood.

As tacrolimus can reduce the clearance of hormonal contraceptives, it is important to be careful when choosing contraceptives.

Data on the interaction of tacrolimus with statins are limited. Clinical observations allow us to conclude that the simultaneous admission with tacrolimus pharmacokinetics of statins does not change.

Experimental studies in animals have shown that tacrolimus Potentially able to reduce clearance and increase the half-life of pentobarbital and phenazone.

Metoclopramide, cisapride, cimetidine, magnesium hydroxide and aluminum hydroxide increase the concentration of tacrolimus in the blood.

Other interactions

The simultaneous use of tacrolimus with drugs that have nephro- or neurotoxicity (eg, aminoglycosides, gyrase inhibitors, vancomycin, sulfamethoxazole + trimethoprim, non-steroidal anti-inflammatory drugs, ganciclovir, acyclovir) can enhance these effects.

As a result of the combined use of tacrolimus with amphotericin B and ibuprofen, the development of tacrolimus nephrotoxicity increased.

As tacrolimus may promote or exacerbate hyperkalemia, high potassium doses or potassium-sparing diuretics should be avoided (amiloride, triamterene, spironolactone).

Immunosuppressants can change the body's response to vaccination: vaccination during treatment with tacrolimus may be less effective. The use of live attenuated vaccines should be avoided.

Binding to proteins

It should be taken into account the possible competitive interaction of tacrolimus with drugs,possessing high affinity for blood plasma proteins (nonsteroidal anti-inflammatory drugs, anticoagulants for oral use, hypoglycemic agents for oral administration).

Special instructions:

In the initial post-transplant period, the following parameters should be regularly monitored: blood pressure, ECG, neurological status and vision, fasting blood glucose, electrolyte concentration (especially potassium), liver and kidney function, hematological parameters, coagulogram, proteinemia level. In the presence of clinically significant changes, correction of immunosuppressive therapy is necessary.

In practice, there were errors in the use of the drug tacrolimus, including unreasonable, unintentional or uncontrolled transfer of patients from one tacrolimus dosage form (standard or prolonged) to another. This led to serious adverse events, including transplant rejection or other side effects that could result from hypo- or hyperimmunosuppression caused by clinically significant differences in tacrolimus exposure.Patients should be on therapy with a single tacrolimus dosage form with an appropriate daily dosage regimen; the change in dosage form or dosage regimen should only be carried out under close supervision of a specialist in the field of transplantology.

In the case of simultaneous use with drugs that are inhibitors CYP3A4 (e.g., telaprevir, boceprevir, ritonavir, ketoconazole, voriconazole, itraconazole, telithromycin or clarithromycin) or inductors CYP3A4 (e.g., rifampicin, rifabutin) - the concentration in the blood of tacrolimus should be monitored for the purpose of timely dose adjustment.

It should avoid the use of herbal preparations containing Hypericum (St. John's wort) or other herbal medicines in the treatment of tacrolimus because of the risk of their possible interactionsth, toabouttGeneral Prospectusandleads to reduce in the blood concentration of tacrolimus and a decrease in the clinical effect of tacrolimus.

With diarrhea, tacrolimus concentrations in the blood can vary significantly; When diarrhea occurs, careful monitoring of tacrolimus concentrations in the blood is necessary.

The combined use of cyclosporine and tacrolimus should be avoided, and caution should be exercised in administering tacrolimus to patients who have previously received ciclosporin.

Cases of ventricular hypertrophy or cardiac hypertrophy reported as cardiomyopathy were observed in patients taking tacrolimus. In most cases, myocardial hypertrophy was reversible and was observed at concentrations (C₀) tacrolimus in the blood, significantly exceeding the maximum recommended. Other factors that increase the risk of this unwanted phenomenon include: the presence of a previous heart disease, the use of glucocorticosteroids, hypertension, impaired renal and hepatic function, infections, hypervolemia, edema. Patients with high risk and receiving intensive immunosuppressive therapy, especially children, before and after transplantation (after 3 and 9-12 months) should carry out echocardiographic and ECG monitoring. If anomalies are detected, consideration should be given to reducing the dose of medicines containing tacrolimus or substituting them for another immunosuppressant.

Tacrolimus may cause lengthening of the interval QT and a violation of the rhythm of the heart such as "pirouette" (bi-directional spindle-shaped ventricular tachycardia). Care should be taken when treating patients with diagnosed or suspected congenital or acquired syndrome of an elongated interval QT, as well as patients receiving drugs extending the interval QT, causing electrolyte disturbances or increasing the concentration (exposure) of tacrolimus in the blood. Attention should also be paid to patients with risk factors for lengthening the interval QT, including patients with episodes of lengthening the interval QT in an individual or family anamnesis, congestive heart failure, bradyarrhythmias and electrolyte disorders.

Perforation of the gastrointestinal tract was noted in patients treated with tacrolimus. Since perforation of the gastrointestinal tract is a medically significant event that can lead to a serious or life-threatening condition, after the appearance of signs or symptoms of perforation, it is necessary to immediately begin treatment activities.

Patients treated with tacrolimus may develop post-transplant lymphoproliferative diseases (PTLZ) associated with the Epstein-Barr virus. With simultaneous application of tacrolimus with antilymphocytic antibodies, the risk of PTLZ increases. There is also evidence of an increased risk of PTFE in patients with the Epstein-Barr virus capsid antigen. Epstein-Barr virus-negative children, young children (<2 years) have an increased risk of developing lymphoproliferative diseases. Therefore, before the appointment of Tacrolimus in this group of patients should be conducted serological examination for the presence of the capsid antigen of the Epstein-Barr virus. In the process of treatment, it is recommended to carry out careful monitoring for the Epstein-Barr virus by polymerase chain reaction (PCR). Positive PCR for the Epstein-Barr virus can persist for several months and is not itself a sign of PTLZ or lymphoma. There are reports of the emergence of a syndrome of reverse reversible encephalopathy (ZOE) on the background of tacrolimus therapy. If patients taking tacrolimus, symptoms appear that are characteristic of the syndrome of SOE: headache, changes in mental state, convulsions and visual disturbances, it is necessary to conduct radiological studies (for example, MRI). When confirming the diagnosis, it is necessary to control blood pressure and immediately stop using tacrolimus. Most patients recover completely after appropriate measures.

In patients receiving immunosuppressive therapy, including tacrolimus, increased risk of opportunistic infections (caused by bacteria, fungi, viruses and protozoa). Among these infections, there is nephropathy associated with BV virus, and associated with JC-virus progressive multifocal leukoencephalopathy (PML). Such infections are often associated with deep suppression of the immune system and can lead to severe and fatal outcomes, which must be taken into account when making a differential diagnosis in patients with signs of impaired renal function or neurological symptoms against immunosuppressive therapy.

Cases of partial red cell aplasia of the bone marrow (PCCA) in patients who received tacrolimus.

All patients had risk factors for PKA, such as the presence of parvovirus B19 infections, diseases or concomitant therapy associated with the possibility of developing PKA.

Immunosuppressive therapy increases the risk of malignant neoplasms, in particular, malignant skin diseases. It is recommended to limit insolation and ultraviolet radiation, wear appropriate clothing, use sunscreens with a high protection factor.

The risk of developing a secondary cancer is unknown.

It is recommended to avoid the use of grapefruit juice in connection with the possibility of increasing the concentration of tacrolimus in the blood.

Tacrolimus is incompatible with polyvinyl chloride (PVC). Tubes, syringes and other equipment used in the preparation of the suspension from the capsules of the preparation should not contain PVC.

Effect on the ability to drive transp. cf. and fur:

Care should be taken when driving vehicles and working with potentially dangerous mechanisms. Tacrolimus can cause visual and neurological disorders.Patients who developed such disorders should not drive a car or work with mechanisms.

Form release / dosage:

Capsules, 0.5 mg, 1.0 mg and 5.0 mg.

Packaging:

1, 7, 10 capsules in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

10, 20, 30, 40, 50 or 100 capsules into cans of polyethylene terephthalate for medicinal products sealed with caps screwed with a first opening control or by a "push-turn" system of polypropylene or polyethylene, or cans of polypropylene for medicines capped with lids with the control of the first opening from polyethylene, or polypropylene cans for medicines, sealed with caps tightened with the control of the first opening of high pressure polyethylene.

One jar or 1, 2, 3, 4, 5 or 10 contour mesh packages together with the instruction for use are placed in a cardboard package (bundle).

Storage conditions:

AT protected from light, at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003770

Date of registration:08.08.2016

Expiration Date:08.08.2021

The owner of the registration certificate:ATOLL, LLC ATOLL, LLC Russia

Manufacturer: & nbsp

OZONE, LLC Russia

Representation: & nbspOZONE LLC OZONE LLC Russia

Information update date: & nbsp08.10.2016

Illustrated instructions

Instructions

Tacrolimus (Tacrolimus)