- instructions for use, doses, side effects, contraindications

Name	Caps. 0.5 mg	Caps. 1 mg	Caps. 5mg
Active substance:
Tacrolimus	0.5 mg	1 mg	5 mg
Excipients:	to obtain a mass of contents, capsules
	65 mg	65 mg	140 mg
[Hypromellose (hydroxypropylmethylcellulose)	0.5 mg	1.0 mg	5.0 mg
Croscarmellose sodium (croscarmoxymethyl cellulose sodium salt)	0.5 mg	1.0 mg	5.0 mg
Lactose monohydrate (milk sugar)	62.85 mg	61.35 mg	123,60 mg
Magnesium stearate	0.65 mg	0.65 mg	1.4 mg
Hard gelatin capsules for white capsules:
Titanium dioxide		2%
Gelatin		up to 100%
for yellow capsules:
Titanium dioxide	1,3333%
Quinoline yellow dye	0,9197%
Dye sunset sunset yellow	0,0044%
Gelatin	up to 100%
for capsules of dark red color:
Titanium dioxide			0,8%
Dye azorubin (carmoazine)			0,14%
Iron oxide red dye			1%
Dye iron oxide yellow			0,2%
Gelatin]			up to 100%

Description:

Hard gelatin capsules №4 yellow (for a dosage of 0,5 mg), №4 of white color (for a dosage of 1 mg), №4 dark red color (for a dosage of 5 mg).

The contents of the capsules are white powder.

Pharmacotherapeutic group:Immunosuppressive agent - calcineurin inhibitor

Pharmacodynamics:

At the molecular level, the effects of tacrolimus are mediated by binding to the cytosolic protein (FKBP12), which is responsible for intracellular accumulation of the drug. Complex FKBR12-tacrolimus specifically and competitively binds to calcineurin and inhibits it,which leads to 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 drug: it 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 (such as interleukins-2, -3 and γ-interferon), interleukin receptor expression -2.

Pharmacokinetics:

Absorption

Tacrolimus is absorbed from the gastrointestinal tract; the main place of absorption is the upper part of the gastrointestinal tract.

Concentrations (Cmah) tacrolimus in the blood reach a peak in about 1 to 3 hours. In some patients, the drug is continuously absorbed for a long period of time, reaching a relative smooth absorption profile. The average values of the absorption parameters are as follows:

Population	Dosage (mg / kg / day)	FROM_mOh (ng / ml)	TS_mOh (hour)	Bioavailability (%)
An adult liver transplant (equilibrium concentration)	0,30	74,1	3,0	21,8 (±6,3)
A liver transplant of the child (equilibrium concentration)	0,30	37,0 (± 26,5)	2,1 (±1,3)	25 (± 20)
Adult kidney transplant (equilibrium concentration)	0,30	44,3 (±21,9)	1,5	20,1 (±11,0)

After oral administration (0.30 mg / kg / day) of the drug to patients with liver transplant, equilibrium tacrolimus concentrations were achieved in most patients for 3 days.

In patients with a liver transplant in a stable state, the bioavailability of tacrolimus was reduced by oral administration of the drug after a moderate-fat meal. There was also a decrease in the area under the pharmacokinetic curve AUC (27%), the maximum concentration of C_mOh (50%) and an increase in TC_mOh (173%) in whole blood. With simultaneous application of the drug with food, the rate and degree of absorption of tacrolimus decreased. Isolation of bile does not affect the absorption of tacrolimus. There is a strong correlation between AUC and the minimum levels of the drug in whole blood upon reaching the equilibrium state, therefore monitoring of the minimum levels of the drug in whole blood can serve to adequately assess the systemic effect of the drug.

In patients with kidney transplant who took tacrolimus immediately after a standard breakfast, the effect on bioavailability was less pronounced. A decrease was noted AUC (2 to 12%) and C_mOh (15 to 38%), and an increase in TC_mOh (38 to 80%) in whole blood.

Isolation of bile does not affect the absorption of tacrolimus.

There is a strong correlation between AUC and the minimum levels of the drug in whole blood upon reaching the equilibrium state, therefore monitoring of the minimum levels of the drug in whole blood can serve to adequately assess the systemic effect of the drug.

Distribution

The distribution of tacrolimus after intravenous (iv) injection of the drug to humans is biphasic.

In the systemic circulation tacrolimus largely associated with erythrocytes. The ratio of the distribution in the whole blood of plasma concentrations is approximately 20: 1. In plasma, the drug is largely bound (> 98.8%) with proteins, mainly with serum albumin and α₁acid glycoprotein. Tacrolimus widely distributed in the body. The equilibrium volume of distribution based on plasma concentrations is approximately 1300 liters (healthy volunteers). The corresponding indicator based on whole blood, on average, is 47.6 liters. Tacrolimus is a preparation with a low level of clearance.

In healthy volunteers, the average value of total clearance, estimated by the concentration of the drug in whole blood, was 2.25 l / h. In adult patients with a liver and kidney transplant, the values of this parameter were 4.1 l / h and 6.7 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.

The half-life of tacrolimus is long and variable. In healthy volunteers, the mean half-life of whole blood is approximately 43 hours. In adult patients and children with liver transplantation, the half-life on average is 11.7 hours and 12.4 hours, respectively, compared to 15.6 hours in adult patients with a kidney transplant.

Metabolism

Using in vitro 8 metabolites were detected, among which only one metabolite possesses significant immunosuppressive activity.

Tacrolimus is largely metabolized by hepatic microsomal cytochrome P-4503A4 isoenzyme (CYP3A4).

Excretion

Following oral administration of tacrolimus labeled ¹⁴With an isotope, most of the radiolabeled drug is excreted with feces.Approximately 2% is excreted in the urine. Less than 1% unchanged tacrolimus was detected in urine and feces, indicating that tacrolimus almost completely metabolized before elimination. The main way of elimination is bile.

Indications:

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

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

Contraindications:

Known hypersensitivity to tacrolimus or other macrolides, to any of the components of the drug.

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

Pregnancy and lactation:

Bebelt: Tacrolimus can penetrate the placenta. There are reports of premature birth (<37 weeks), as well as cases of spontaneously resolved hyperkalemia in newborns (8 of 111 (7.2%) of newborns). Since the safety of tacrolimus in pregnant women is not sufficiently established, this drug should not be administered to pregnant women, unless the intended benefit of treatment for the mother justifies 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 function of the kidneys).

Breast-feeding: tacrolimus penetrates into breast milk, and therefore women receiving this drug should cancel breastfeeding.

Dosing and Administration:

Drug therapy tacrolimus requires careful monitoring by personnel with the appropriate qualifications and having the necessary equipment at their disposal. Assign tacrolimus or changes in immunosuppressive therapy can be made only by physicians 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 taking capsules tacrolimus, you need to 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. Dose choice tacrolimus should be based, first of all, on a clinical assessment 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 administered orally; If necessary, the contents of the capsules can be mixed with water and injected through a nasogastric tube. Children under the age of 3 are difficult to swallow a capsule, so after opening the capsule, its contents are mixed with a small amount of water and given to drink to the baby.

The daily dose is divided into 2 doses (morning and evening). Capsules should be taken immediately after removing them from the blister pack, on an empty stomach or 1 hour before or 2-3 hours after ingestion.

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 rejection - adults

Oral therapy with tacrolimus should begin with a dosage of 0.1-0.2 mg / kg / day, dividing this dose into 2 divided doses (for example, in the morning and in the evening). The drug should be started approximately 12 hours after the operation is completed.

If the patient's condition does not allow taking the medication internally, intravenous therapy should begin at a dose of 0.01-0.05 mg / kg / day, injecting the medication as an intravenous infusion for 24 hours.

Preventing rejection - children

The initial dose for oral administration of 0.3 mg / kg / day should be divided into 2 divided 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, you should start IV therapy at a dose of 0.05 mg / kg / day, as an IV infusion for 24 hours.

Supportive therapy - adults and children

In the course of maintenance therapy, the dosage of tacrolimus usually decreases. In some cases it is possible to cancel preparations of concomitant immunosuppressive therapy, leaving tacrolimus as a monotherapy. 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 - adults and children

To treat episodes of rejection, higher doses of tacrolimus should be used in combination with additional corticosteroid therapy and short courses of administration of mono / polyclonal antibodies.If signs of toxicity are noted, a dose reduction of tacrolimus may be required.

Kidney Transplantation

Prevention of rejection - adults

Oral therapy with tacrolimus should begin with a dose of 0.2-0.3 mg / kg / day, dividing this dose into 2 divided doses (for example, in the morning and in the evening). The drug should be started approximately 24 hours after the operation is completed.

If the patient's condition does not allow taking the medication internally, intravenous therapy should begin at a dose of 0.05-0.1 mg / kg / day, injecting the drug in the form of an IV infusion for 24 hours.

Preventing rejection - children

Supportive therapy - adults and children

In the course of maintenance therapy, the dosage of tacrolimus usually decreases. In some cases it is possible to cancel preparations of concomitant immunosuppressive therapy, leaving tacrolimus as a basic component of dual therapy.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 higher doses of tacrolimus in combination with additional glucocorticosteroid therapy and short courses of mono / polyclonal antibodies. If signs of toxicity appear, a dose reduction of tacrolimus may be required.

For information on transferring patients with cyclosporine therapy to tacrolimus see the manual at the end of this section, "Adjusting the dose of the drug in specific 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 drug use tacrolimus) or without the appointment of antibodies in clinically stable patients. Following the induction of antibodies, oral therapy with tacrolimus capsules should be started at a dose of 0.075 mg / kg / day, divided into two doses (for example, in the morning and in the evening), within 5 days after the operation, once the patient's clinical condition is stabilized.If the patient's condition does not allow taking the drug inside, you should start IV therapy with a dose of 0.01-0.02 mg / kg / day, as an IV infusion for 24 hours. 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 the drug mycophenolate mofetil and corticosteroids, or sirolimus and corticosteroids.

Prevention of rejection - 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 to achieve a tacrolimus concentration in whole blood of 15-25 ng / ml, at the first clinical opportunity, the patient should be transferred to oral taking the drug.The initial oral dose should be 0.3 mg / kg / day and be administered 8-12 hours after discontinuation of intravenous infusion.

Following the induction of antibodies, oral administration of capsrols of tacrolimus should begin with a dose of 0.1-0.3 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 dosage of tacrolimus usually decreases. 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 higher doses of tacrolimus in combination with additional glucocorticosteroid therapy and short courses of mono / polyclonal antibodies.

When transferring patients to tacrolimus capsules, the initial daily dose (for adults - 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 ).

Adjusting the dose of the drug in specific patient populations

Patients with hepatic insufficiency: patients with severe hepatic insufficiency may need a dose reduction in order to maintain a minimum level of the drug within the recommended grades.

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

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: there is currently no evidence of the need to adjust the dose of the drug for elderly patients.

Transfer from therapy with cyclosporine: The concomitant use of cyclosporine and tacrolimus may increase the half-life of cyclosporin and enhance toxic effects. Therefore, care must be taken when transferring patients from cyclosporine to tacrolimus therapy.Treatment with tacrolimus should begin after an assessment of the concentrations of cyclosporine in the patient's blood and the clinical state of the patient. The use of the drug should be postponed if there is an elevated level of cyclosporine in the patient's blood. In practice, treatment with tacrolimus is administered 12-24 hours after cessation of cyclosporine. After transferring the patient to tacrolimus it is necessary to continue monitoring the levels of cyclosporine in the patient's blood in connection with the possibility of violations in the clearance of cyclosporine.

Recommendations for achieving the required concentration level of the drug in whole blood

The choice of the dose of tacrolimus is based on the clinical assessment of rejection and tolerability of the drug 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 the 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 themethod of evaluation.

In the early period after the operation, the minimum levels of tacrolimus in the whole blood should be monitored. When administered orally to determine the minimum levels of the drug in the blood, it is necessary to obtain blood samples 12 hours after taking the drug, immediately before the next dose. The frequency of monitoring the level of the drug in the blood should depend on the clinical needs.

As tacrolimus is a preparation with a low level of clearance, adjustment of the dosing regimen can take several days until the moment when the changes in blood levels in the blood become obvious. The 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 monitor the minimum levels of tacrolimus in the blood after changing the dose of the drug, changing the immunosuppressive regimen, or after sharing with drugs that may affect the concentration of tacrolimus in whole blood.

The results of the analysis of clinical studies suggest that,that it is possible to successfully treat most patients if the minimum level of tacrolimus in the blood does not exceed 20 ng / ml.

In clinical practice, during the early period after transplantation, the minimum level of the drug in whole blood usually ranged from 5-20 ng / ml in liver transplant recipients and 10-20 ng / ml in patients with a kidney and heart transplant. Later, during maintenance therapy after liver, kidney and heart transplantation, tacrolimus concentration in the blood varies from 5 to 15 ng / ml.

Side effects:

Many of the undesirable drug reactions claimed below are reversible and / or reduced with reduced dosage. When administered orally, the incidence of adverse drug reactions is lower than with IV. The following are the reactions in descending order, depending on the frequency of development: very often (≥1 / 10); often (≥1 / 100, <1/10); infrequently (≥1 / 1000, <1/100); rarely (≥1 / 10000, <1/1000); very rarely (<1/10000, including single cases), is unknown (can not be estimated based on available data).

Heart Disease:

often: coronary artery ischemia, tachycardia;

infrequently: ventricular arrhythmia and cardiac arrest, heart failure, cardiomyopathy, ventricular hypertrophy, supraventricular arrhythmia, increased heart rate, abnormalities in ECG parameters, heart rate and heart rate abnormalities;

rarely: exudative pericarditis;

very rarely: changes in the echocardiogram, lengthening of the interval QT, disturbance of the rhythm of the heart such as "pirouette" (bidirectional spindle-shaped ventricular tachycardia).

Violations from 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, clotting and bleeding disorders, insufficiency of the hematopoietic system, incl. pancytopenia, neutropenia;

rarely: thrombotic thrombocytopenic purpura, hypoprothrombinemia;

unknown: partial red cell aplasia, agranulocytosis, hemolytic anemia.

Disturbances from the nervous system:

very often: tremor, headache;

often: convulsions, impaired consciousness, paresthesia and dysesthesia, peripheral neuropathy, 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.

Disorders from the side of the organ of vision:

often: blurred vision, photophobia, eye diseases;

infrequently: cataract;

rarely: blindness.

Hearing disorders and labyrinthine disturbances:

often: tinnitus;

infrequently: hearing loss;

rarely: sensorineal deafness;

very rarely: hearing loss.

Disturbances from the respiratory system, chest and mediastinal organs:

often: dyspnea, lung parenchyma, pleural effusion, pharyngitis, cough, nasal congestion, rhinitis;

infrequently: respiratory failure, respiratory diseases, 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 bleeding, stomatitis and ulceration of the oral mucosa, ascites, vomiting,gastrointestinal and abdominal pain, dyspeptic disorders, constipation, flatulence, bloating, loose stool, symptoms of gastrointestinal disturbances and abdominal distension;

infrequently: paralytic obstruction of the intestine, peritonitis, acute and chronic pancreatitis, increased activity of amylase in the blood, reflux disease, violation of gastric emptying;

rarely: partial intestinal obstruction, pseudocysts of the pancreas.

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, rashes, alopecia, acne, hyperhidrosis;

infrequently: dermatitis, photosensitivity;

rarely: toxic epidermal necrolysis (Lyell's syndrome);

very rarely: Stevens-Johnson Syndrome.

Disturbances from the musculoskeletal and connective tissue:

often: arthralgia, muscle cramps, pain in the limbs, back pain;

infrequently: joint disease.

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, other disorders of electrolytes;

infrequently: dehydration, hypoproteinemia, hyperphosphataemia, hypoglycemia.

Infectious and parasitic diseases:

In patients receiving tacrolimus, as in the treatment with other immunosuppressive drugs, the risk of developing infectious diseases (viral, bacterial, fungal, protozoal) is increased. The course of previously diagnosed infectious diseases may worsen.

Cases of nephropathy associated with VC virus, as well as cases of progressive multifocal leukoencephalopathy (PML) associated with JCvirus, in patients receiving immunosuppressants, including tacrolimus.

Trauma, intoxication and complications of manipulation:

often: primary transplant dysfunction.

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 are at increased 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 diseases and malignant neoplasms of the skin.

Vascular disorders:

very often: arterial hypertension;

often: bleeding, thromboembolism and ischemic disorders, peripheral vascular disorders, arterial hypotension;

infrequently: myocardial infarction, deep vein thrombosis of the extremities, shock.

General disorders and disorders at the site of administration:

often: asthenic conditions, febrile conditions, edema, pain and discomfort, increased alkaline phosphatase activity in the blood, increased body weight, impaired body temperature perception;

infrequently: multiple organ failure, influenza-like syndrome, impaired perception of the temperature of the environment, a feeling of squeezing in the chest, a sense of anxiety, worsening of well-being, increased lactate dehydrogenase activity in the blood, weight loss;

rarely: a feeling of thirst, loss of balance (falling), a feeling of restraint in the chest, obstruction of movement, ulcer;

very rarely: an increase in the mass of adipose tissue.

Immune system disorders:

In patients receiving tacrolimus, allergic and anaphylactic reactions were observed.

Disorders from the liver and bile ducts:

often: changes in hepatic enzyme activity and impaired liver function,pathological changes in functional hepatic tests, cholestasis and jaundice, hepatocellular injuries and hepatitis, cholangitis;

rarely: thrombosis of the hepatic artery, veno-occlusive disease of the liver;

very rarely: hepatic insufficiency, stenosis of the bile duct.

Violations of the genitals and mammary glands:

infrequently: dysmenorrhea and uterine bleeding.

Disorders of the psyche:

very often: insomnia;

general: symptoms of anxiety, confusion and disorientation, depression, depressed mood, affective disorders, nightmares, hallucinations, mental disorders;

infrequently: psychotic disorders.

Overdose:

Symptoms: tremor, headache, nausea, vomiting, infection, urticaria, lethargy, increased blood urea nitrogen concentrations and hypercreatininaemia, increased ALT activity.

Treatment: symptomatic; after oral administration - gastric lavage and / or intake of adsorbents (Activated carbon) if these measures are taken soon after taking the drug. There is no specific antidote. Given the high molecular weight, poor solubility in water and a pronounced binding to red blood cells and plasma proteins, dialysis is ineffective.In individual patients (with a very high concentration of the drug in the blood plasma), hemofiltration or diafiltration were effective, reducing toxic drug concentrations. The clinical experience of overdose management is limited.

Interaction:

Metabolic interactions

Tacrolimus, located in the systemic blood stream, is metabolized in hepatic cytochrome CYP3A4. There is also evidence of gastrointestinal metabolism CYP3A4 in the intestinal wall. Simultaneous administration of medicinal or plant preparations that inhibit or induce CYP3A4, can affect the metabolism of tacrolimus and, thus, reduce or increase tacrolimus levels in the blood. Therefore, it is recommended to monitor the concentration of tacrolimus in the blood, monitor the interval QT (with the help of electrocardiography), as well as renal function and possible side effects, when the therapy is carried out simultaneously with the drugs that affect the CYP3A4 for timely correction of the dose of tacrolimus and maintenance of its exposure.

Inhibitors of Metabolism

Clinically, for the following substances, tacrolimus elevation in blood was demonstrated:

Strong interactions were observed with antifungal agents, such as ketoconazole, fluconazole, itraconazole and voriconazole, antibiotics of the macrolide group (for example, erythromycin), HIV protease inhibitors (e.g., ritonavir, nelfinavir, saquinavir) or hepatitis C virus protease inhibitors (telaprevir, boceprevir). The simultaneous use of these drugs may require a reduction in the dose of tacrolimus in almost all patients.

Weaker interactions were observed with the following drugs: clotrimazole, clarithromycin, josamycin, nifedipine, nicardipine, diltiazem, verapamil, amiodarone, danazol, ethinyl estradiol, omeprazole and nefazodone.

Based on research results in vitro it was demonstrated that the following drugs are potential inhibitors of tacrolimus metabolism: bromocriptine, cortisone, dapsone, ergotamine, gestodene, lidocaine, mephenytoin, miconazole, midazolam, nilvadipine, norethisterone, quinidine, tamoxifen, troleandomycin.

It is noted that grapefruit juice increases the level of tacrolimus in the blood, so joint use should be avoided.

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

Inductors of metabolism

Clinically, for the following substances, a decrease in tacrolimus in the blood was demonstrated:

Strong interactions were observed with the following drugs: rifampicin, phenytoin, St. John's wort. Joint use with these drugs may require an increase in the dose of tacrolimus in almost all patients.

Clinically significant interactions were also observed with phenobarbital.

A decrease in the level of tacrolimus in the blood was observed with the use of maintenance doses of corticosteroids.

It is shown that high doses of prednisolone or methylprednisolone, prescribed for the treatment of acute rejection, both increase and lower the level of tacrolimus in the blood.

Such drugs as carbamazepine, metamizole and isoniazid also reduce the concentration of tacrolimus in the blood.

Effect of tacrolimus on the metabolism of other drugs

Tacrolimus is an inhibitor CYP3A4, so its simultaneous use with drugs that are metabolized CYP3A4, can affect the metabolism of such drugs.

It was shown that the half-life of cyclosporin increased with simultaneous application with tacrolimus.In addition, synergistic / additive nephrotoxic effects may develop. For these reasons, combined use of cyclosporin and tacrolimus is not recommended for the administration of tacrolimus to patients who previously received ciclosporin.

It is noted that taking tacrolimus helps to increase the level of phenytoin in the blood.

As tacrolimus can reduce the clearance of steroid contraceptives and lead to an increase in the exposure of hormones, special attention should be given to the decision on measures to protect against pregnancy.

At present, there is insufficient information on the interaction between tacrolimus and statins. The available data indicate that the pharmacokinetics of statins does not change with simultaneous application with tacrolimus. Studies in animals have shown that tacrolimus can reduce clearance and increase the half-life of phenobarbital and phenazone.

Other interactions

The combined use of tacrolimus with drugs with nephrotoxic or neurotoxic effects may increase the level of toxicity (eg, aminoglycosides, gyrase inhibitors, vancomycin, sulfamethoxazole + trimethoprim, NSAIDs, ganciclovir or acyclovir).

Increased nephrotoxicity was observed after taking amphotericin B and ibuprofen in combination with tacrolimus.

Since tacrolimus treatment may be accompanied by the development of hyperkalemia, or may exacerbate pre-existing hyperkalemia, excessive intake of potassium or potassium-sparing diuretics should be avoided (for example, amiloride, triamterene or spironolactone).

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

Binding to proteins

Tacrolimus largely binds to blood plasma proteins. Consideration should be given to possible interactions with other drugs that have a high affinity for blood proteins (eg, NSAIDs, oral anticoagulants, or oral antidiabetics).

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,concentration of electrolytes (especially potassium), indicators of liver and kidney function, parameters of clinical blood analysis, coagulation and determination of proteins in blood plasma. When detecting clinically significant abnormalities, 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 graft 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.

Use of herbal preparations containing St. John's wort (St. John's wort) or other herbal preparations in the treatment of tacrolimus should be avoided because of the risk of their possible interaction, which leads to a decrease in blood concentrations of tacrolimus and a decrease in the clinical effect of tacrolimus. Since the concentration of tacrolimus in the blood can change significantly when diarrhea occurs, additional monitoring of the tacrolimus concentration is necessary in this case.

The combined use of cyclosporin and tacrolimus should be avoided in the appointment of tacrolimus to patients who have previously received ciclosporin.

In rare cases, ventricular hypertrophy or hypertrophy of the heart septum was reported, which was reported as cardiomyopathy. Most of the cases were reversible and were observed primarily in children with a significant excess of the maximum recommended level of tacrolimus concentration in the blood.Other risk factors for these clinical conditions, including pre-existing heart disease, use of corticosteroids, hypertension, renal or hepatic dysfunction, infections, fluid overload and edema, have been identified. Therefore, high-risk patients, especially young children and those undergoing intensive immunosuppression, should be examined, such as echocardiography and ECG before and after transplantation (for example, 3 months before and then 9-12 months after) . In detecting abnormalities, consideration should be given to reducing the dose of tacrolimus or substituting it for another immunosuppressive therapy.

The application of tacrolimus may lead to lengthening of the interval QT, but at the same time there is no data for the development of "pirouette tachycardia" (torsades de pointes). Caution should be exercised in patients with suspected or acquired long-interval syndrome QT, receiving drugs that extend the interval QT, causing electrolyte disturbances or increasing the concentration (exposure) of tacrolimus 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.

In patients who received tacrolimus, possibly perforation of the gastrointestinal tract; development of posttransplantation lymphoproliferative diseases (PTLZ) associated with the Epstein-Barr virus. With simultaneous application of tacrolimus with antilymphocytic antibodies (for example, daclizumab, basiliximab) the risk of PTFE 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, children of younger age (<2 years) have an increased risk of developing lymphoproliferative diseases. Thus, in this group of patients, a serological examination should be conducted for the presence of Epstein-Barr virus capsid antigen, serological status should be established prior to treatment with tacrolimus. During treatment, careful monitoring is recommended for the Epstein-Barr virus. Positive polymerase chain reaction (PCR) for the Epstein-Barr virus can persist for months anditself is not a testimony of PTLZ or lymphoma.

In patients who received tacrolimus, there was a development of the syndrome of posterior reversible encephalopathy (ZOE). If patients taking tacrolimus, symptoms that indicate an SOE syndrome, such as headache, changes in mental state, convulsions, and visual impairment, should be identified (eg, MRI). If the SOE syndrome is confirmed, it is recommended that blood pressure control be performed and the tacrolimus is immediately discontinued. Most patients recover completely after appropriate measures.

Patients receiving immunosuppressive therapy, including tacrolimus, have an increased risk of opportunistic infections (bacterial, fungal, viral and protozoal). Among these infections, there is nephropathy associated with BV virus, and associated with JC-virus progressive multifocal leukoencephalopathy (PML). These infections are often associated with a deep suppression of the immune system and can lead to severe and fatal outcomes,which must be taken into account when conducting a differential diagnosis in patients with signs of impaired renal function or neurological symptoms on the background of 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 infection, disease or concomitant therapy associated with the possibility of developing PKA.

As with other immunosuppressive drugs, due to the potential risk of developing malignant changes on the skin, exposure to sunlight and UV radiation should be limited, protecting the skin with clothing and using creams with a high protective factor.

As with other immunosuppressive drugs, the likelihood of developing a secondary cancer is unknown.

Tacrolimus is incompatible with polyvinyl chloride (PVC). If the contents of the capsules are to be injected through a nasogastric tube, the latter should not contain polyvinyl chloride.

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

Tacrolimus can cause visual and neurological disorders.Patients who developed such disorders should not drive a car or work with mechanisms. This effect can be exacerbated by the simultaneous administration of tacrolimus with alcohol.

Form release / dosage:Capsules, 0.5 mg, 1 mg and 5 mg.

Packaging:

10 capsules per contour cell packaging made of polyvinylchloride film and aluminum foil printed lacquered.

1, 2, 3, 5, 10 contour cell packs of 10 capsules are placed in a sealed aluminum bag together with a bag containing a desiccant.

For 10 capsules in a contour mesh packaging of PA / AL / PVC and aluminum foil printed lacquered.

For 50 capsules in polyethylene bottles, with polypropylene caps with control of the first opening with an insert of silica gel.

Each bottle or a sealed aluminum bag, or 1, 2, 3, 5, 10 contiguous cell packs of PA / AL / PVC and foil of aluminum printed lacquer of 10 capsules together with the instruction for use is placed in a pack of cardboard.

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

For capsules with a dosage of 0.5 mg - 2 years.

For capsules with dosages of 1 mg and 5 mg - 3 years.

After opening the primary package (sealed aluminum bag) - 1 year.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003661

Date of registration:06.06.2016

Expiration Date:06.06.2021

The owner of the registration certificate:VEROPHARM SA VEROPHARM SA Russia

Manufacturer: & nbsp

VEROPHARM SA Russia

Representation: & nbspVEROPHARM, AO VEROPHARM, AO Russia

Information update date: & nbsp09.05.2017

Illustrated instructions

Instructions

GREECE® (Grastiva®)