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

Tacrolimus monohydrate *	0.51 mg	1.02 mg	5.11 mg
in terms of tacrolimus Excipients	0.50 mg	1.00 mg	5.00 mg
Povidon-KZO	4.00 mg	4.00 mg	4.00 mg
Croscarmellose sodium	25.00 mg	25.00 mg	25.00 mg
Magnesium stearate	1.40 mg	1.40 mg	1.40 mg
Lactose Hard gelatin capsules № 3	up to 140 mg	up to 140 mg	up to 140 mg
titanium dioxide	1,3333 %	2,0000 %	0,3000 %
dye iron oxide yellow	0,1000%	-	-
dye iron oxide red	-	-	1,0000%

gelatin up to 100%

* The amount of tacrolimus monohydrate is calculated from the actual water content, the average mass is corrected with lactose.

Description:

Dosage 0.5 mg: hard gelatin capsules number 3, body and cap - white with a creamy shade of color.

Dosage 1 mg: hard gelatin capsules number 3, body and cap - white. Dosage of 5 mg: hard gelatin capsules number 3, body and cap - red. The contents of the capsules are white powder.

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 (FKBP12). The complex of RKBP12-tacrolimus specifically and competitively binds to the calf neurin 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: suppresses the formation of cytotoxic lymphocytes, which are mainly responsible for graft rejection, reduces T-cell activation, T-helper dependent T cell proliferation, and the formation of lymphokines (such as interleukins-2, -3 and gamma-interferon), expression the interleukin-2 receptor.

Pharmacokinetics:

Absorption

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

With oral administration of the drug, the average time to reach the maximum concentration (Tstah) of tacrolimus in the blood is 1-3 hours. In some patients tacrolimus continuously 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 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 "concentration-time" (AUC) (27%), the maximum concentration (C_max) (50%) and an increase in Tc_max (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 C_max (by 15-38%), and an increase in Tc_max(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%) to proteins, mainly with serum albumin and a-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 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 tacrolimus concentrations in whole blood, was 2.25 l / h. In adult patients with a liver, kidney and heart transplant, the values of this parameter were 4.1 l / h, 6.7 and 3.9 l / h, respectively.In children with a liver transplant, the overall 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 (T1/2) tacrolimus is long and variable. In healthy volunteers, the mean Tg value of whole blood is approximately 43 hours. In adult patients and children with a liver transplant, Tc on average is 11.7 and 12.4 hours, respectively, compared to 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 with a 14C isotope, the majority of the radiolabeled drug was excreted by the intestine. Approximately 2% is excreted by the kidneys, while about 1% of tacrolimus was determined unchanged. Consequently, tacrolimus before almost completely metabolized, the main way of elimination was 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:

Hypersensitivity to tacrolimus, auxiliary components of the drug, macrolides. Deficiency of lactase, lactose intolerance, glucose-galactose malabsorption.

Pregnancy and lactation:

Pregnancy

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,when 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).

Breastfeeding period

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

Dosing and Administration:

Therapy with Tacrolimus STADA requires careful monitoring by personnel with the appropriate qualifications and the necessary equipment. To appoint Tacrolimus STADA or to make changes in immunosuppressive therapy only doctors having experience of carrying out immunosuppressive therapy in patients with transplanted organs can.

If you miss taking capsules Tacrolimus STADA 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 STADA is usually used in combination with other immunosuppressants. The dose may vary depending on the regimen of immunosuppressive therapy. The choice of the dose of Tacrolimus STADA should be based, first of all, on the 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 capsule form 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 is divided into 2 doses (morning and evening) in equal doses. Capsules should be taken immediately after they are removed from the blister. Desiccant (package with silica gel), embedded in the packaging, is not edible.

Capsules are washed down with a liquid, preferably water. To achieve maximum absorption, capsules are recommended to be taken on an empty stomach, 1 hour before 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 therapy with Tacrolimus STADA capsules should be started at 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, then 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, then it is necessary to start IV therapy with tacrolimus in the form of an infusion solution 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 Tacrolimus STADA should be divided into two doses (eg morning and evening).

If the clinical state of the patient does not allow taking the medicines inward,then it is necessary to start IV therapy with tacrolimus 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, doses of Tacrolimus STADA are usually reduced. In some cases, it is possible to cancel preparations of concomitant immunosuppressive therapy, leaving Tacrolimus STADA as monotherapy. If 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, Tacrolimus STADA should be used in higher doses 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 Tacrolimus STADA capsules, the same initial doses are recommended, as with primary immunosuppression. Information on transferring patients with cyclosporine therapy to Tacrolimus STADA is given below.

Kidney Transplantation Prevention of rejection Adults

Oral therapy with Tacrolimus STADA capsules should be started at a dose of 0.20-0.30 mg / kg / day, divided into two doses (for example, 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 the medication to be taken orally, it is necessary to initiate IV therapy with tacrolimus in the form of an infusion solution at 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 Tacrolimus STADA should be divided into two doses (eg morning and evening).

If the patient's clinical condition does not allow taking the medicines inward, then it is necessary to start iv / tacrolimus therapy in the form of a solution for infusions in a dose of 0.075-0.100 mg / kg / day as infusion within 24 hours.

Supportive therapy Adults and children

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

Treatment of rejection reaction Adults and children

When transferring patients to capsule therapy Tacrolimus STADAnd the same initial doses are recommended, as with primary immunosuppression. Information on transferring patients with cyclosporine therapy to Tacrolimus STADA is given below.

Heart transplantation Prevention of rejection Adults

Tacrolimus STADA can be used in combination with induction therapy with antibodies (which allows delaying the initiation of Tacrolimus STADA) or without antibodies in clinically stable patients. Following induction by antibodies, oral capsule therapy Tacrolimus TPATDA should be started at a dose of 0.075 mg / kg / day divided into two doses (eg, in the morning and in the evening) for 5 days after the operation as soon as the patient's clinical condition is stabilized.

If the patient's condition does not allow taking the drug inside, it is necessary to start iv therapy with tacrolimus in the form of a solution for infusions 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 combined with mycophenolate mofetil and glucocorticosteroids, or sirolimus and glucocorticosteroids.

Children

After heart transplantation in children, primary immunosuppression with Tacrolimus STADA can be carried out both in combination with antibody induction, and independently. In those cases when induction is not carried out with antibodies and tacrolimus injected IV in the form of a solution for infusions, 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 the oral administration of the drug.The initial dose for oral administration should be 0.30 mg / kg / day and should be administered 8-12 hours after discontinuation of intravenous infusion.

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

Supportive therapy

Adults and children

During maintenance therapy, the dose of the drug Tacrolimus TITA DAnd usually reduce. 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

To treat episodes of rejection, Tacrolimus STADA should be used in higher doses in combination with additional glucocorticosteroid therapy and short courses of mono / polyclonal antibodies.

When transferring patients to Tacrolimus STADA capsules, the initial daily dose for Adults-0.15 mg / kg / day, for children - 0,20-0,30 mg / kg / day should be divided into two doses (for example, in the morning and in the evening).

Information on transferring patients with cyclosporine therapy to Tacrolimus STADA is given below.

Recommended doses for treatment of rejection after allotransplantation of other organs

Recommendations for dosing of Tacrolimus STADA for patients after lung, pancreas and small intestine allotransplantation are based on data from selected prospective clinical trials.

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

After allotransplantation of sub-utero glands the initial dose is

0.20 mg / kg / day.

After allotraisplaitation of the small intestine the initial dose of the drug is 0.30 mg / kg / day.

Correction of dose of the drug in special populations of patients

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

The pharmacokinetics of tacrolimus does not change with the function of the kidneys, so patients with renal insufficiency correction of the dose is not required. However, due to the presence of nephrotoxic action in tacrolimus, it is recommended to carefully monitor the kidney function (including creatinine content in the blood serum, creatine kinase (CK) and diuresis).

Children to achieve similar concentrations of the drug in the blood, doses are usually required that are 1.5-2 times higher than doses for adults.

Currently, there is no data on the need to adjust the dose of the drug in elderly patients.

Transfer from cyclosporine to drug treatment Tacrolimus STADA

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. Treatment with capsules Tacrolimus STADA should be started after an assessment of the concentrations of cyclosporine in the blood and the clinical state of the patient. Transition to Tacrolimus STADA should be postponed in the presence of elevated concentrations of cyclosporine in the patient's blood. Practice shows that Tacrolimus STADA is administered 12-24 hours after the removal of cyclosporine. After the transfer of the patient, it is necessary to continue monitoring the concentrations of cyclosporin in the patient's blood in connection with the possibility of a disruption in the clearance of cyclosporine.

Recommendations for monitoring the therapeutic concentration of tacrolimus in the blood

The choice of the dose of Tacrolimus STADA 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). 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. Tacrolimus STADA is a drug with a low clearance value, so after correction of 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 2 times 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 Tacrolimus STADA, 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 Tacrolimus STADA capsules is the most successful in those cases when the minimum concentration of tacrolimus in the blood does not exceed 20 ng / ml. When interpreting data on the concentration 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 frequency of detection: very often (> 1/10), often (> 1/100 to <1/10), infrequently (> 1/1000 to <1 / 100), rarely (from> 1/10 000 to <1/1 000), very rarely (<1/10 000), the frequency is unknown (to establish the frequency of which, the data is not enough).

Heart Disease:

often: coronary artery ischemia, tachycardia;

infrequently: ventricular arrhythmia and cardiac arrest, heart failure, cardiomyopathy, ventricular hypertrophy, supraventricular arrhythmia, heart palpitations, abnormalities in ECG parameters, violation of heart rate and rhythm;

rarely: exudative pericarditis; very rarely: changes in the echocardiogram.

Violations from the blood and lymphatic system:

often: anemia, leukopenia, thrombocytopenia, leukocytosis, decreased or increased hemoglobin and / or hematocrit;

infrequently: coagulopathies, blood clotting disorders and bleeding, 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 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 is rare: increased muscle tone, increased intracranial pressure; very rarely: myasthenia gravis.

Disturbances on the part of the organ of sight often: blurred vision, photophobia, eye diseases; infrequently: cataract; rarely: blindness.

Hearing disorders and labyrinthine disturbances:

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: dyspnea, 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 bleeding, stomatitis and ulceration of the oral mucosa, ascites, vomiting, gastrointestinal and abdominal pain, dyspepsia, constipation, flatulence, sensations of bloating and rasping in the abdomen, loose stool, symptoms of disorders of the gastrointestinal tract;

infrequent: paralytic intestinal obstruction (paralytic ileus), peritonitis, acute and chronic pancreatitis, increased activity of amylase in the blood, gastroesophageal reflux disease, violation of the evacuation function of the stomach; rarely: subileus, pancreatic pseudocysts.

Disturbances from the liver and bile ducts

often: increased activity of "liver" enzymes, violations of liver function,

cholestasis, jaundice, liver cell damage, hepatitis, cholangitis;

rarely: thrombosis of the hepatic artery, obliterating endophlebitis of the hepatic veins;

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

Disorders from the kidneys and urinary tract very often: impaired renal function;

often: renal failure, including acute renal failure, oliguria,

acute tubular necrosis, toxic nephropathy, urinary syndrome, disorders with

the sides 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 electrolyte disorders;

infrequently: dehydration, hypoproteinemia, hyperphosphataemia, hypoglycemia.

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 JCvirus, in patients receiving immunosuppressants, including tacrolimus.

Trauma, intoxication and complications of manipulation: often: primary graft dysfunction;

There have been cases of errors in the use of tacrolimus drugs, 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 circulation 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 stiffness in the chest, difficulty moving;

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

Immune system disorders:

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

Violations of the genitals and mammary glands: infrequently: dysmenorrhea and uterine bleeding Disorders of the psyche: very often: insomnia;

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

infrequently: psychotic disorders

Overdose:

Information on overdose is limited. Several episodes of overdose have been reported in patients taking tacrolimus. Symptoms included tremor, headache, nausea, vomiting, infection, urticaria, lethargic state, increased blood urea nitrogen concentration, hypercreatininemia, increased activity of alanine aminotransferase.

Currently there are no antidotes to tacrolimus. In case of an overdose, symptomatic treatment should be performed.

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 is metabolized by isoenzyme CYP3A4. Simultaneous intake of substances that inhibit or induce isoenzyme CYP3A4, can affect the metabolism of tacrolimus, and accordingly increase or decrease the concentration of tacrolimus in the blood. Therefore, in order to maintain adequate and permanent exposure of tacrolimus, it is recommended that the concentration of tacrolimus in the blood be monitored and, if necessary, the dose of Tacrolimus STADA should be adjusted.

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 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 noted that grapefruit juice increases the concentration of tacrolimus in the blood, therefore joint use should be avoided.

Lansoprazole and ciclosporin can potentially inhibit SURCA4-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. With the simultaneous use 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 isoenzyme CYP3A4 and with simultaneous administration may affect the drugs metabolized by isoenzyme CYP3A4. The half-life of cyclosporin with simultaneous application with tacrolimus increases. 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 concentration 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.

Amphotericin B, ibuprofen increase the risk of developing tacrolimus nephrotoxicity.

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

Possible competitive interactions between tacrolimus and drugdrugs that have a high affinity for plasma proteins (non-steroidal anti-inflammatory drugs, anticoagulants for oral use, hypoglycemic agents for oral administration).

Special instructions:

In the initial post-transplant period should be carried out regularly monitors the following parameters: blood pressure, ECG, neurologic status and condition of view, fasting blood glucose level, the concentration of electrolytes (especially potassium), liver and kidney function, hematology, coagulation, proteinemii 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 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 (eg, telaprevir, boceprevir, ritonavir, ketoconazole, voriconazole, itraconazole, telithromycin or clarithromycin) or inductors CYP3A4 (eg, 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.

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

Joint use of cyclosporine and tacrolimus should be avoided, with the appointment of 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. 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.

The application of tacrolimus may lead to lengthening of the interval QT, but at the same time there is no evidence of the development of "pirouette tachycardia" (torsades de pointes). Caution should be exercised in patients with diagnosed or suspected congenital syndrome of elongated QT.

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 the drug Tacrolimus SHTADA in this group of patients should conduct a serological study 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.

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 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 with 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.

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 Tacrolimus STADA 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 STADA can cause visual and neurological disorders. Patients who developed such disorders should not drive a car or work with mechanisms.

Form release / dosage:

Capsules of 0.5 mg, 1 mg, 5 mg.

10 capsules in a contour squeeze box (blister) from a polyvinylchloride / polyvinylidene chloride film and aluminum foil. 5 blisters and a bag of granular silica gel in a package of aluminum foil. A package of aluminum foil together with instructions for use in a pack of cardboard.

Packaging:(10) - blisters [packings, cellular, planimetric] (5) - bags made of aluminum foil-packs cardboard

Storage conditions:

Store at a temperature not exceeding 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

1 year after opening the aluminum foil bag.

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

Terms of leave from pharmacies:On prescription

Registration number:LP-002606

Date of registration:29.08.2014

The owner of the registration certificate:SHTADA Artznajmittel AGSHTADA Artznajmittel AG Germany

Manufacturer: & nbsp

Laboratorios Cinfa, S.A. Spain

Representation: & nbspNizhpharm, JSCNizhpharm, JSCRussia

Information update date: & nbsp02.09.2015

Illustrated instructions

Instructions

Tacrolimus of Stade (Tacrolimus-Stada)