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

Capsule shell composition: gelatin 23.2112 mg, purified water 4.06 mg, sodium lauryl sulfate 0.0224 mg, methyl parahydroxybenzoate 0.224 mg, propyl parahydroxybenzoate 0.056 mg, titanium dioxide 0.42 mg, colorant blue brilliant (E 133) 0.0064 mg.

Dosage 1 mg

Active substance: tacrolimus monohydrate 1,022 mg in terms of tacrolimus 1 mg.

Excipients: lactose monohydrate 77.228 mg, talc 4.75 mg, hypromellose 1 mg, croscarmellose sodium 1 mg.

Capsule shell composition: gelatin 23.3266 mg, purified water 4.06 mg, sodium lauryl sulfate 0.0224 mg, methyl parahydroxybenzoate 0.224 mg, propyl parahydroxybenzoate 0.056 mg, titanium dioxide 0.3078 mg, brilliant blue dye (E 133) 0.0002 mg.

Dosage 5 mg

Active substance: tacrolimus monohydrate 5.11 mg in terms of tacrolimus 5 mg.

Excipients: lactose monohydrate 66.14 mg, talc 3.75 mg, hypromellose 5 mg, croscarmellose sodium 5 mg.

Capsule shell composition: gelatin 23.328 mg, water purified 4.06 mg, sodium lauryl sulfate 0.0224 mg, methyl parahydroxybenzoate 0.224 mg, propyl parahydroxybenzoate 0.056 mg, titanium dioxide 0.3078 mg, color yellow "sunset sunset" (E 110) 0.0018 mg.

Description:

Dosage 0.5 mg: hard, opaque gelatin capsules number 5 light-blue. The contents of capsules are white or almost white powder.

Dosage 1 mg: hard, opaque gelatin capsules number 5 light green-blue. The contents of capsules are white or almost white powder.

Dosage of 5 mg: hard, opaque gelatin capsules number 5 light orange color. The contents of capsules are white or almost 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 cumulation of the drug. The complex of RCRM12-tacrolimus specifically and competitively interacting with calcineurin inhibits it, which leads to calcium-dependent inhibition of T-cell signaling transduction pathways and prevention of 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 and 3 and γ-interferon), expression of interleukin-2 receptor.

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_mOh) tacrolimus in the blood is 1-3 hours. In 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%), the maximum concentration (C_mOh) (50%) and an increase in TC_mOh (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_mOh (by 15-38%) and an increase in vehicle traffic_mOh (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

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 volunteers, the average value of total clearance, estimated by the concentration of tacrolimus in whole blood, is 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 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_1/2an 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, most 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 elimination almost completely metabolized, the main way of elimination was bile.

Indications:

Prevention and treatment of the rejection reaction of liver, kidney and heart allograft, including resistant to standard regimens of immunosuppressive therapy.

Contraindications:

Hypersensitivity to tacrolimus or other macrolides, lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

Carefully:

There is no information.

Pregnancy and lactation:

The results of preclinical and clinical studies show that the drug can penetrate the placenta. Some data on the application of tacrolimus in transplanted patients indicate 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 function of the kidneys).

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:

The drug is administered orally.

Therapy with the drug requires careful monitoring by personnel with 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.

If you miss taking capsules of the drug Tacrolimus it is necessary 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, the drug Tacrolimus usually used in combination with other immunosuppressants. The dose may vary depending on the regimen of immunosuppressive therapy.

The dose of the drug must be adjusted depending on the individual needs of the patient, taking into account the results of monitoring the drug concentrations in the patient's blood.

It is recommended to divide the daily dose of the drug into two doses (for example, in the morning and in the evening). Capsules should be taken immediately after they are removed from the blister pack. Capsules must be swallowed whole by washing with liquid (preferably with water). If required, the contents of the capsules can be dissolved in water and injected through a nasogastric tube. Children up to 3 years of the drug should be taken, after opening the capsule and mixing its contents with water. To achieve maximum absorption, capsules should be taken on an empty stomach (fasting) or at least 1 hour 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.

Dosing recommendations

Liver transplantation

Prevention of rejection

Adults

Oral therapy with the drug should begin with a dose of 0.1-0.2 mg / kg / day, dividing this dose (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 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 for oral administration of 0.3 mg / kg / day 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 course of maintenance therapy, the dose of the drug is usually lowered. In some cases it is possible to cancel preparations of concomitant immunosuppressive therapy, leaving tacrolimus as a basic monotherapy. Improving the patient's condition after transplantation can alter the pharmacokinetics of tacrolimus, which in turn may require dose adjustment.

Treatment of rejection reaction - adults and children

To treat the rejection reaction, it is necessary to use higher doses of the drug in combination with additional glucocorticosteroid therapy (GCS) 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 begin with a dose of 0.2-0.3 mg / kg / day, dividing it 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 taking the drug inside, it is necessary to begin intravenous therapy at a dose of 0.05-0.1 mg / kg / day as a continuous 24-hour infusion.

Children

The initial dose of 0.3 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 from a dose of 0.075-0.1 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 becomes possible to cancel the concomitant immunosuppressants, leaving the drug Tacrolimus as a basic component of dual therapy. When 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 the rejection reaction, it is necessary to increase doses of tacrolimus, the appointment of additional therapy for SCS and short courses of mono / polyclonal antibodies. If signs of toxicity appear, a dose reduction of tacrolimus 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."

Heart transplantation

Primary immunosuppression

Adults

Tacrolimus can be used in combination with induction therapy with antibodies (thatallows delaying the start of the drug) or without the appointment of antibodies in 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."

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 minimum concentration of the drug within the recommended values.

Patients with renal insufficiency: Do not need a dose adjustment. The pharmacokinetics of tacrolimus does not change with the function of the kidneys. However, due to the presence of nephrotoxic action in tacrolimus, it is recommended to closely monitor the kidney function (including serum creatinine concentration, creatinine clearance and 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.

Translation from therapy with cyclosporine

Simultaneous use of cyclosporine and tacrolimus may increase the period of excretion of cyclosporine and enhance toxic effects. Therefore, care must be taken when transferring patients from cyclosporine to tacrolimus therapy. Treatment 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 in the presence of elevated concentrations of cyclosporine in the patient's blood. In practice, treatment with tacrolimus begins 12-24 hours after cessation 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 disorders in the 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).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, the minimum concentrations of tacrolimus in whole blood should be monitored. When administered orally to determine the minimum concentrations 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 drug concentrations in the blood should depend on 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 changes in the concentration of the drug in the blood become obvious. The minimum concentrations of the drug in the blood should be monitored approximately twice per week during the early post-transplant period and then periodically during maintenance therapy. It is also necessary to monitor the minimum concentrations of tacrolimus in the blood after changing the dose of the drug,changes in the immunosuppressive regimen or after joint use with drugs that may affect the concentration of tacrolimus in whole blood.

The results of clinical studies indicate that the treatment with capsules of tacrolimus is 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 posttransplant 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:

In connection with the characteristics of the underlying disease and a large number of drugs used simultaneously after transplantation, the profile of undesirable reactions of immunosuppressants is difficult to establish accurately.

Many of the undesirable reactions presented below are reversible and / or reduced with a lower dose. Oral reception is associated with a lower risk of adverse reactions compared with intravenous administration of the drug.

According to the World Health Organization (WHO), unwanted reactions are classified according to their frequency of development as follows: very often (≥ 1/10), often (from ≥> 1/100 to <1/10), infrequently (from ≥ 1 / 1000 to <1/100), rarely (from ≥ 1/10000 to <1/1000), very rarely (<1/10000); the frequency is unknown - it is not possible to establish the frequency of occurrence from the available data.

Heart Disease:

often: tachycardia, ischemic coronary disorders;

infrequently: ventricular arrhythmias and cardiac arrest, heart failure, cardiomyopathies, ventricular hypertrophy, supraventricular arrhythmias, heart palpitations, abnormal electrocardiography (ECG), disturbances in rhythm and heart rate and heart rate;

rarely: pericardial effusion;

rarely: pathological changes on the echocardiogram, lengthening of the interval QT on an electrocardiogram, a disturbance of the rhythm of the heart such as "pirouette" (bidirectional spindle-shaped ventricular tachycardia).

Vascular disorders:

Often: arterial hypertension;

often: bleeding, thromboembolic and ischemic complications, peripheral circulatory disorders, arterial hypotension;

infrequently: a heart attack, deep vein thrombosis of the extremities, shock.

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 coagulogram, pancytopenia, neutropenia;

rarely: thrombotic thrombocytopenic purpura, hypoprothrombinemia;

frequency 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;

rarely: increased muscle tone; rarely: myasthenia gravis.

Vision disorders:

often: blurred vision, photophobia, eye diseases, visual impairment;

infrequently: cataract;

rarely: blindness.

Hearing disorders and labyrinthine disorders:

Often: noise (ringing) in the ears;

infrequently: hearing loss;

rarely: sensorineal deafness;

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;

infrequently: respiratory insufficiency, respiratory tract disorders, asthma;

rarely: acute respiratory distress syndrome.

Disorders from the gastrointestinal tract:

Often: diarrhea, nausea;

often: inflammatory diseases of the digestive tract, gastrointestinal ulcers and perforations, gastrointestinal bleeding, stomatitis and ulceration of the oral mucosa, ascites, vomiting, gastrointestinal and abdominal pain, indigestion, constipation, flatulence, sensations of swelling and enlargement in the abdomen, loose stools , symptoms of gastrointestinal disturbances;

infrequently: paralytic intestinal obstruction (paralytic ileus), peritonitis, acute and chronic pancreatitis, increased amylase activity in the blood, gastroesophageal reflux disease, impaired gastric evacuation function;

rarely: subileus, pancreatic pseudocysts.

Disorders from the kidneys and urinary tract:

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;

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);

rarely: Stevens-Johnson syndrome.

Disturbances from musculoskeletal and connective tissue:

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

infrequently: articular disorders.

Disorders from the endocrine system:

rarely: hirsutism.

Disorders from the metabolism and nutrition:

Often: hyperglycemia, hyperkalemia, diabetes mellitus;

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:

Allergic reactions: in patients taking tacrolimus, allergic and anaphylactic reactions were observed.

Infectious and parasitic diseases:

Against the background of tacrolimus therapy, as well as other immunosuppressants, the risk of local and generalized infectious diseases (viral, bacterial, fungal, protozoal) increases. The course of previously diagnosed infectious diseases may worsen. Cases of nephropathy associated with BV virus, as well as progressive multifocal leukoencephalopathy (PML) associated with JC- a virus, were observed against immunosuppressive therapy, including tacrolimus therapy.

Injuries, intoxication and complications of manipulation:

often: primary transplant dysfunction.

In practice, there were 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, and also recorded cases of graft rejection (according to available data, the frequency can not be estimated).

Benign, malignant and unspecified neoplasms (including cysts and polyps):

Patients receiving immunosuppressive therapy have a higher risk of malignant tumors. When tacrolimus was used, both benign and malignant neoplasms appeared, including the Epstein-Barr virus (EBV) - associated lymphoproliferative diseases and skin cancer.

General disorders and disorders at the site of administration:

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

infrequently: multiorgan insufficiency, flu-like syndrome, impaired perception of the temperature of the environment, a feeling of squeezing in the chest, a sense of anxiety, deterioration of health, increased lactate dehydrogenase activity in the blood, weight loss;

rarely: thirst, loss of balance (falling), sensation of stiffness in the chest, difficulty in movement, ulcer;

rarely: weight gain of adipose tissue.

Disturbances from the liver and bile ducts:

often: increase in the level of hepatic enzymes, violations of liver function, pathological changes in functional liver tests, cholestasis, jaundice, liver cell damage and hepatitis, cholangitis;

rarely: thrombosis of the hepatic artery, obliterating endophlebitis of the hepatic veins; rarely: hepatic failure, stenosis of the hepatic ducts.

Disorders from the reproductive system:

infrequently: dysmenorrhea and uterine bleeding.

Disorders of the psyche:

very often: insomnia;

often: anxiety, confusion and disorientation, depression, depressed mood, affective disorders, nightmares, hallucinations, mental disorders;

infrequently: psychotic disorders.

Overdose:

The clinical experience of overdose management is limited. Several cases of overdose were noted, with the following symptoms: tremor, headache, nausea, vomiting, infection, urticaria, lethargy, increased blood urea nitrogen concentrations and hypercreatininaemia, increased activity of alanine transferase (ALT).

There is no specific antidote to tacrolimus. In case of an overdose, standard measures and symptomatic treatment should be taken.

Due to the high molecular weight, poor solubility in water and binding to red blood cells and blood plasma proteins to a large extent, it is expected that dialysis will not be effective if tacrolimus is overdosed. In individual patients with very high concentrations of the drug in the blood plasma, hemofiltration and diafiltration were effective, reducing the toxic concentrations of the drug. In cases of intoxication after oral administration of the drug, gastric lavage and / or the use of adsorbents (for example, activated carbon) can help if these measures are taken shortly after taking the drug.

Interaction:

Metabolic interactions

Tacrolimus, located in the systemic circulation, is metabolized by the isoenzyme CYP3A4. When taken orally tacrolimus is also metabolized in the intestinal cytochrome system CYP3A4. Simultaneous reception of medicines, incl. medicinal plants known for their inhibitory or inducing action on the isoenzyme CYP3A4, can affect the metabolism of tacrolimus and thus, 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

Clinically proven that the following substances increase the concentration of tacrolimus in the blood:

Significant interaction was observed with antifungal agents (ketoconazole, fluconazole, itraconazole and voriconazole), macrolide antibiotics (erythromycin), HIV protease inhibitors (incl. ritonavir, nelfinavir, saquinavir) or hepatitis C virus protease inhibitors (telaprevir, boceprevir). Simultaneous administration of tacrolimus with these drugs may require a reduction in the dose of tacrolimus.

Less pronounced interaction was observed with clotrimazole, clarithromycin, josamycin, nifedipine, nicardipine, diltiazem, verapamil, amiodarone, danazol, ethinyl estradiol, omeprazole and nefazodone.

In vitro the following drugs showed themselves as potential inhibitors of tacrolimus metabolism: bromocriptine, cortisone, dapsone, ergotamine, gestodene, lidocaine, mephenytoin, miconazole, midazolam, nilvadipine, norethisterone, quinidine, tamoxifen, troleandomycin.

It has been reported that the concentration of tacrolimus in the blood increases with the use of grapefruit juice, it is recommended to avoid their joint intake.

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

Inductors of metabolism

Clinically proven that the following substances reduce the concentration of tacrolimus in the blood:

Significant interaction was observed with rifampicin, phenytoin, St. John's wort perforated. The simultaneous administration of tacrolimus with these drugs requires an increase in the dose of tacrolimus. Clinically significant interactions were observed with phenobarbital. Supportive doses of glucocorticosteroids reduce the concentration of tacrolimus in the blood.

High doses of prednisolone and methylprednisolone, used to treat acute graft rejection, contribute to a decrease or increase in tacrolimus concentration in the blood.

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

Effect of tacrolimus on the metabolism of other drugs

Tacrolimus is an inhibitor of the isoenzyme CYP3A4, therefore simultaneous reception of tacrolimus with drugs metabolized by isoenzyme CYP3A4, can affect the metabolism of these drugs.

Increases the half-life of cyclosporine, with the possible increase in toxic effects. It is not recommended simultaneous administration of cyclosporine and tacrolimus in patients who received early ciclosporin. Synergistic / additive nephrotoxic effects may also occur.For these reasons, simultaneous administration of cyclosporine and tacrolimus is not recommended. It is advisable to use caution when transferring patients from cyclosporine to tacrolimus therapy (the concentration of cyclosporin in the blood should be monitored).

Tacrolimus increases the concentration of phenytoin in the blood plasma.

As tacrolimus can reduce the clearance of hormonal contraceptives, thus leading to an increase in the impact of these drugs, this should be taken into account when selecting methods of contraception.

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.

Preclinical data show that tacrolimus can potentially reduce the 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 that lead to side effects

Simultaneous reception of tacrolimus with neuro- and nephrotoxic drugs (incl.aminoglycosides, gyrase inhibitors, vancomycin, sulfamethoxazole + trimethoprim, non-steroidal anti-inflammatory drugs, ganciclovir, acyclovir) increases the risk of neuro- and nephrotoxicity.

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

As tacrolimus can promote or enhance hyperkalemia, high doses of potassium or potassium-sparing diuretics should be avoided (including 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.

Due to the high degree of binding of tacrolimus to plasma proteins, it is possible to compete with other drugs with high affinity for plasma proteins (including non-steroidal anti-inflammatory drugs, anticoagulants for oral use, hypoglycemic agents for oral administration).

Incompatibility

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.

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), hepatic and renal function, hematological parameters, coagulogram, plasma protein concentration blood. In the presence of clinically significant changes, correction of immunosuppressive therapy is necessary.

In practice, there were errors in the use of tacrolimus medications, 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.The patient should be kept on one of the medicinal forms of tacrolimus with the appropriate dosing regimen: the change in dosage form or dosing regimen should be carried out only under the supervision of a specialist in the field of transplantology.

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

When using drugs tacrolimus should avoid the appointment of herbal products containing St. John's wort (Hypericum perfiratum), as well as other herbal remedies that can cause a decrease (change) in the concentration of tacrolimus in the blood and adversely affect the clinical effect of the drug.

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

Simultaneous use of cyclosporine and tacrolimus should be avoided, and caution should be exercised when treating tacrolimus patients who previously received ciclosporin.

Cases of ventricular hypertrophy or interventricular septum hypertrophy, reported as cardiomyopathy, were rarely, but were observed in patients taking tacrolimus. In most cases, myocardial hypertrophy was reversible, was observed primarily in children at concentrations (FROM₀) tacrolimus in the blood, exceeding recommended. Other factors that increase the risk of this unwanted phenomenon include: the presence of a previous heart disease, the use of corticosteroids, hypertension, renal and hepatic dysfunction, 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 medications 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 must be taken when treating patients with a suspected or diagnosed congenital or acquired syndrome of an elongated interval QT, as well as patients receiving drugs that extend the interval QT, causing electrolyte disturbances or increasing the concentration (exposure) of tacrolimus blood. It should also pay attention 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.

The perforation of the gastrointestinal tract was noted in patients receiving tacrolimus therapy. 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 (EBV). With simultaneous application of tacrolimus with antilymphocytic antibodies (for example, daclizumab, basiliximab) the risk of PTFE increases. Children under 2 years old, as well as children with a negative test for the capsid antigen of the Epstein-Barr virus, are considered to be at high risk of development of PTLZ. Therefore, before the appointment of the drug Tacrolimus In this group of patients, a serological study should be conducted for the presence of the Epstein-Barr virus capsid antigen. 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 months and by itself is not evidence 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.

In patients receiving immunosuppressive therapy, including tacrolimus, increased risk of opportunistic infections (caused by bacteria, fungi, viruses, 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 or 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 tumors. 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.

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

It is noted that grapefruit juice increases the concentration of tacrolimus in the blood by inhibiting activity CYP3A4.

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

During the treatment period, it is recommended to refrain from engaging in potentially dangerous activities that require a high concentration of attention and speed of psychomotor reactions (including driving).

Form release / dosage:

Capsules, 0.5 mg; 1 mg or 5 mg.

Packaging:

10 capsules per blister of aluminum foil and aluminum laminated foil. For 1, 2 or 3 blisters with instructions for use in a pack of cardboard.

For 100 or 500 tablets in a plastic bag.1 package in a can of HDPE with silica gel, sealed with aluminum foil with a polyethylene coating, with a screw cap. On the bank stick a label from paper label or writing or from polymer materials, self-adhesive. For 1, 6, 12 or 24 cans, together with the corresponding number of instructions for use, are placed in a group box - a box of corrugated cardboard (for hospitals).

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-004160

Date of registration:28.02.2017

Expiration Date:28.02.2022

The owner of the registration certificate:Lock-Beta Pharmaceuticals (I) Pvt.LtdLock-Beta Pharmaceuticals (I) Pvt.Ltd India

Manufacturer: & nbsp

LOK-BETA PHARMACEUTICALS (I), Pvt. Ltd. India

Representation: & nbspLock-Beta Pharmaceuticals (I) Pvt.LtdLock-Beta Pharmaceuticals (I) Pvt.Ltd

Information update date: & nbsp30.03.2017

Illustrated instructions

Instructions

Tacrolimus (Tacrolimus)