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

Capsule contents: active ingredient: tacrolimus monohydrate 0.511 mg (equivalent to tacrolimus 0.500 mg); Excipients: hypromellose 0.300 mg, lactose monohydrate 48.489 mg, croscarmellose sodium 0.300 mg, magnesium stearate 0.400 mg.

Capsule shell: body: titanium dioxide (E171) 0.600 mg, sodium lauryl sulfate 0.015 mg, sorbitan laurate 0.015 mg, gelatin 23.97 mg; lid: iron dye oxide yellow (E172) 0.03 mg, titanium dioxide (E171) 0.16 mg, sodium lauryl sulfate 0.01 mg, sorbitan monolaurate 0.01 mg, gelatin 16.19 mg.

Dosage: 1.0 mg

Capsule contents: active ingredient: tacrolimus monohydrate 1.022 mg (equivalent to tacrolimus 1,000 mg); Excipients: hypromellose 0.600 mg, lactose monohydrate 47.378 mg, croscarmellose sodium 0.600 mg, magnesium stearate 0.400 mg.

Capsule shell: body: titanium dioxide (E171) 0.600 mg, sodium
lauryl sulfate 0.015 mg, sorbitan laurate 0.015 mg, gelatin 23.97 mg;

lid: iron oxide, yellow oxide (E172) 0.067 mg, iron dye oxide red (E172) 0.008 mg, iron dye oxide black (E172) 0.008 mg, titanium dioxide (E171) 0.25 mg, sodium lauryl sulfate 0.01 mg, sorbitan monolaurate 0 , 01 mg, gelatin 16.047 mg.

Dosage of 5.0 mg

Capsule contents: active ingredient: tacrolimus monohydrate 5,110 mg (equivalent to tacrolimus 5,000 mg); Excipients: hypromellose 3,000 mg, lactose monohydrate 236.890 mg, croscarmellose sodium 3,000 mg, magnesium stearate 2,000 mg.

Capsule shell: body: titanium dioxide (E171) 0.74 mg, sodium lauryl sulfate 0.02 mg, sorbitan laurate 0.02 mg, gelatin 29.82 mg; lid: iron oxide red dye (E172) 0.08 mg titanium dioxide (E171) 0.4 mg, 0.015 mg sodium lauryl sulfate, sorbitan monolaurate 0.015 mg, 19.89 mg gelatin.

Description:

Dosage 0.5 mg: Hard gelatin capsules No. 4 with an opaque white body and a lighter of light yellow color.

Dosage 1.0 mg: Hard gelatin capsules No. 4 with an opaque white body and a lid of light brown color.

Dosage 5.0 mg: Hard gelatin capsules No. 3 with an opaque white body and an orange lid.

The contents of capsules are white or almost white powder.

Pharmacotherapeutic group:immunosuppressive agent.

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. Complex FKVP12-tacrolimus specifically and competitively binds to calcineurin and inhibits it, which leads for inhibition of calcium-dependent T-cell signal transduction pathways, thereby preventing, transcription of a discrete group of lymphokine genes.

Tacrolimus is a highly immunnosupressivnym preparation: inhibits the formation of cytotoxic lymphocytes, which are mainly responsible for graft rejection, reduces the activation of T-cell-dependent T-helper cell proliferation and the formation of lymphokines (such as interleukins-2 - 3 and gamma-interferon), the expression of interleukin-2 receptor.

Pharmacokinetics:

Absorption

Tacrolimus is absorbed from the gastrointestinal tract; the main place of absorption is the upper part of the gastrointestinal tract. Concentrations (Cmax) of 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 relatively flat absorption profile. The average values of the absorption parameters are as follows:

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

(equilibrium

concentration)

After oral administration of the drug (0.3 mg / kg / day) in most patients with liver transplant, equilibrium tacrolimus concentrations were achieved within 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 "concentration-time" curve AUC (27%), a maximum concentration of C max (50%), and an increase in Tmax (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 pronounced correlation between AUC and minimum concentrations of the drug in whole blood upon reaching the equilibrium state, therefore monitoring of the minimum concentrations of the drug in whole blood can serve to adequately assess the systemic effect of the drug.

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 the distribution in the whole blood of plasma concentrations is approximately 20: 1. In plasma, the drug is largely associated with proteins (> 98.8%), 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 drug with a low level of clearance. In healthy volunteers, the average value of total clearance, estimated by the concentrations 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 transplants, 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 identified, among which only one metabolite possesses significant immunosuppressive activity. Tacrolimus is largely metabolized by the hepatic microsomal isoenzyme CYP3A4.

Excretion

After oral administration of tacrolimus labeled with a 14C isotope, the majority of the radiolabeled drug was excreted by the intestine. Approximately 2% is excreted by the kidneys. Less than 1% of 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 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;

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

Pregnancy and lactation:

The results of preclinical and clinical studies show that the drug can penetrate the placenta. Since the safety of tacrolimus in pregnant women is not sufficiently established, this drug should not be given to pregnant women, unless the intended benefit of treatment for the mother justifies the potential risk to the fetus.

Based on the results obtained during the research, it was shown that tacrolimus excreted in breast milk. Since it is impossible to exclude the undesirable effects on newborn children, women who take tacrolimus, should not breast-feed the baby.

Dosing and Administration:

Tacrosel® is used orally.

If required, content capsules can be dissolved in water and enter through a nasogastric tube.

Dose of the drug is necessary adjust depending on of individual needs patient, taking into account the results monitoring of concentrations in patient's blood. It is recommended to divide the daily oral 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 should be swallowed by washing with liquid (preferably with water). To achieve maximum absorption, capsules should be taken on an empty stomach (on an empty stomach) or at least 1 hour or 2-3 hours after ingestion.

There was no noticeable effect of food on the absorption of the drug in patients with a kidney transplant.

Dosing recommendations

Liver transplantation

Primary immunosuppression adults

Oral therapy with Tacrosel® should be started at a dose of 0.10-0.20 mg / kg / day, by dividing this dose (eg, in the morning and in the evening). The drug should be started approximately 12 hours after the operation is completed. Primary immunosuppression is children

The initial dose for oral administration of 0.3 mg / kg / day should be divided into 2 divided doses (eg morning and evening).

Supportive therapy adults and children

During maintenance therapy, the dose of Tacrosil® is usually reduced.In some cases, it is possible to cancel preparations of concomitant immunosuppressive therapy, leaving Tacrose * as a basic monotherapy. Improving the patient's condition after transplantation can alter the pharmacokinetics of tacrolimus, which in turn may require dose adjustment. To achieve similar concentrations of the drug in the blood, children usually require doses 1.5-2 times higher than doses for adults.

Treated rejection reactions - adults and children

To treat the rejection reaction, higher doses of Tacrosel^f at combination with additional glucocorticosteroid therapy and short courses of administration of mono- / polyclonal antibodies. If signs of toxicity are noted, a dose reduction may be required.

Kidney Transplantation

Primary immunosuppression adults

Patients who do not receive baseline therapy (aimed at stimulating antibodies) by oral therapy with Tacrosel® should be started at a dose of 0.3 mg / kg / day, dividing this dose into two doses (for example, in the morning and in the evening). The drug should be started within approximately 24 hours after the operation is completed.

Patients receiving basal therapy are advised to start oral administration of the drug at a dose of 0.20 mg / kg / day, dividing it into two doses (for example, in the morning and in the evening).

Primary immunosuppression is children Before the operation, the drug is prescribed to children at a dose of 0.15 mg / kg / day.

After the operation, it is necessary to prescribe therapy with Tacrosil in an initial dose of 0.3 mg / kg / day, dividing it into two doses.

Supportive therapy adults and children

In the course of maintenance therapy, doses of Tacrosil® are usually reduced. In some cases, it may be necessary to cancel preparations concomitant immunosuppressive therapy, leaving Tacrose * as a basic monotherapy. Improvement of the patient's condition after transplantation can change the pharmacokinetics of tacrolimus and, as a consequence, require correction of the dose of the drug.

Basically, the principle of dosing of the drug should be based on the results of a clinical evaluation of the rejection reaction and drug tolerance in each patient individually. If the clinical signs of rejection reaction obvious, it is necessary to consider changing the regime of immunosuppressive therapy.

For achievements Similar concentrations of the drug in the blood of children usually require doses (in terms of body weight) in 1,5-2 times higher than for adults.

Treatment of rejection reaction adults and children

To treat the rejection reaction, the doses were increased tacrolimus, appointed additional therapy glucocorticosteroids and short courses introduction of mono/ polyclonal antibodies. If signs of toxicity occur, a dose reduction may be required tacrolimus.

Reaction rejection heart transplant

Initial therapy of rejection reaction

The initial dose of the drug for oral administration is 0.3 mg / kg / day, divided into two reception (for example, in the morning and in the evening). Correction of dose of the drug in special populations of patients Patients with severe hepatic insufficiency: can need a dose reduction for in order to maintain a minimum concentration drug within the recommended range.

Patients from renal insufficiency: not required 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).

Elderly patients: in the present time there is no evidence of the need to adjust the dose of the drug for elderly patients. Translation from therapy with cyclosporine

Accompanying application of cyclosporine and tacrolimus can 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 be started 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 are elevated concentrations cyclosporine in the patient's blood. In practice, tacrolimus treatment started 12-24 hours after cessation applications cyclosporine. Therapy should begin with the initial oral dose recommended for primary immunosuppression in a specific allograft (both in adult patients and in children).After the transfer of the patient, you must continue monitoring of concentrations of cyclosporine in the patient's blood in connection with the possibility of disorders in the clearance of cyclosporine.

Recommendations for achieving the necessary concentrations preparation at whole blood.

In the early period after the operation should be monitored the minimum concentration of tacrolimus in whole blood. When administered orally to determine the minimum concentration of the drug in the blood, it is necessary to obtain blood samples 12 hours after taking the medication, immediately before the next dose. The frequency of monitoring drug concentrations in the blood should depend on clinical needs. Since Tacrosel® is a preparation with a low clearance level, adjusting the dosage regimen may take several days before the changes in blood concentrations of the drug become apparent.

The minimum concentrations the drug in the blood should be monitored approximately twice a week during the early posttransplant period and then periodically during maintenance therapy. It is also necessary control the minimum concentrations tacrolimus in the blood after changing the dose of the drug, changing the immunosuppressive regimen, or after sharing with drugs that can affect the concentration tacrolimus in whole blood.

The results of the analysis of clinical research suggest that you can successfully to administer the majority patients, if the minimum tacrolimus concentration in the blood are maintained below 20 ng / ml.

In clinical practice during early period after minimal transplantation concentration of the drug in a blood usually fluctuated within 5-20 ng / ml in recipients liver transplant and 10-20ng / ml in patients with a kidney transplant.

Consequently, in the course of maintenance therapy concentration of the drug in the blood should be 5-15 ng / ml, as in recipients of a liver transplant, and kidney transplant.

Side effects:

Many of the following side effects are reversible and / or decrease with a lower dose. According to the World Health Organization (WHO) undesirable Effects are classified according to their frequency of development as follows: very often (> 1/10), often (> 1/100 to <1/10), infrequently (from> 1/1000 to <1/100), rarely (from > 1/10000 to <1/1000),very rarely (<1/10000); frequency is unknown - according to available data, establish frequency not n possible m. Violations from the side of serdia often: tachycardia; infrequently: ventricular arrhythmias and cardiac arrest, heart failure, cardiomyopathies, hypertrophy ventricles, soup sweetscurly arrhythmias, rapid palpitation, abnormal ECG indices, disorders rhythm and frequency heart rate and pulse; rarely: pericardial effusion; rarely: abnormal parameters of the echocardiogram, elongation interval QT, violation of the rhythm of the heart such as "pirouette."

Vascular disorders Often: arterial hypertension;

often: ischemic coronary disorders, bleeding, rhomboembolic and ischemic complications, violations peripheral blood circulation, arterial hypotension; infrequently: heart attack, deep vein thrombosis, shock.

Violations of the blood and lymphatic system often: anemia, leukopenia, thrombocytopenia, leukocytosis, a decrease or increase in the level of hemoglobin and / or hematocrit; infrequently: coagulopathy, abnormalities in indicators coagulograms, pancytopenia, neutropenia; rarely: thrombocytopenic purpura, hypotrophinia; frequency is unknown: agranulocytosis, hemolytic anemia, partial to racemose appendix.

Disturbances from the nervous system

Often: tremor, headache; often: convulsive syndrome different genesis, impaired consciousness, paresthesia and dysesthesia, peripheral neuropathy, dizziness, violation of writing, nervous system disorders; infrequently: coma, hemorrhages in central nervous system and disorders cerebral blood circulation, paralysis and paresis, encephalopathy, speech and articulation disorders, amnezia;

rarely: increased muscle tone;

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 disorders often: noise in 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 gastro-intestinal tract

Often: diarrhea, nausea;

often: inflammatory diseases of the gastrointestinal tract (GIT), gastrointestinal ulcers and perforations, gastrointestinal bleeding, stomatitis and ulceration of the oral mucosa, ascites, vomiting, gastrointestinal and abdominal pain, indigestion, constipation, flatulence, feelings of bloating and enlargement in the abdomen, loose stool, symptoms of gastrointestinal disturbances; infrequently: paralytic intestinal neprisConvergence (paradigmatic ileus), peritonitis, acute and chronic pancreatitis, increased amidase activity in blood plasma, gastroesophageal reflux disease, impaired gastric evacuation function;

rarely: subileus, pancreatic pseudocysts.

Disturbances from the liver and bile ducts often: increased activity hepatic enzymes, liver dysfunction, cholestasis, jaundice, liver cell damage and hepatitis, cholangitis;

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

rarely: hepatic insufficiency, biliary stenosis ducts.

Infringements from kidneys and urinary tract

Often: function violation kidney;

often: renal failure, acute renal failure, oliguria, acute tubular necrosis, toxic nephropathy, urinary syndrome, disorders with the side of the bladder and urethra;

infrequently: anuria, hemolytic uremic syndrome;

rarely: nephropathy, hemorrhagic cystitis.

Violations from the sexual organs and mammary gland

infrequently: dysmenorrhea and uterine bleeding.

Disturbances from the skin and subcutaneous tissue

often: itching, rash, alopecia, acne, hyperhidrosis;

infrequently: dermatitis, photosensitization;

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

rarely: Stevens-Johnson.

Disturbances from musculoskeletal and connective tissue

often: arthralgia, muscular 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, hyperkalaemia, diabetes mellitus;

often: hypomagnesemia, hypophosphatemia, hypokalemia, hypocalcemia, hyponatremia, hypervolemia, hyperuricemia, decreased appetite, anorexia, metabolic acidosis, hyperlipidemia, hypercholesterolemia, hypertriglyseasepidemyata, electrolyte disturbances;

infrequently: Oozeology, hypoproteinemia, hyperphosphatemia, hypoglycemia.

Immune system disorders

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

Disorders of the psyche

Often: insomnia; often: anxiety, confusion consciousness and disorientation, depression, depressed mood, emotional disorders, nightmares, hallucinations, mental disorders; infrequently: psychotic disorder.

Infectious and parasitic diseases

Against the background of tacrolimus, as well as other and immunosuppressant therapy,increased risk of local and generalized infectious diseases (viral, bacterial, fungal, protozoal). May worsen the course of previously diagnosed infectious diseases. Cases of nephropathy associated with BV-virus, as well as progressive multifocal leukoencephalopathies (NML), associated with JCvirus, were observed on background immunosuppressive therapy, including capsule therapy.

Trauma, intoxication and complications of manipulation

often: primary dysfunction transplant.

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

Benign, malignant and unspecified neoplasms

Patients, receiving immunosuppressive therapy, have more tall risk malignant tumors. When application of both benign and malignant neoplasms, including the Epstein-Barr virus (VVU) -associated with lymphoproliferative diseases and skin cancer, was noted.

General disorders and disorders at the site of administration

often: asthenia, febrile conditions, edema, pain and discomfort, increased alkaline phosphatase activity in plasma blood, weight gain body, violation perception of body temperature; infrequently: multi-organ 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 well-being, rise lactate dehydrogenase activity in blood plasma, weight loss;

rarely: thirst, loss of balance (falls), a feeling of stiffness in the thoracic cage, embarrassment movement, ulcer;

rarely: weight gain adipose tissue.

Overdose:

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

There is no specific antidote to tacrolimus.If an overdose develops, standard stopping 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 with an overdose of tacrolimus. In individual patients with very high concentrations of the drug in blood plasma, hemofiltration and diafiltration were effective, decreasing the toxic concentrations of the drug. In cases of development of intoxication after oral administration of the drug, gastric lavage and / or absorption of adsorbents (such as Activated carbon).

Interaction:

Pharmacokinetic interactions

Tacrolimus is largely metabolized hepatic microsomal isoenzyme CYP3A4. Simultaneous reception of substances, inhibiting or inducing isoenzymes CYP3A4, can affect the metabolism of tacrolimus, and, accordingly, increase or reduce the concentration of tacrolimus in the blood plasma. Tacrolimus largely binds to blood plasma proteins.Possible interactions with other drugs that have a high affinity for blood proteins should be considered (eg, NSAIDs, oral anticoagulants or hypoglycemic agents for oral administration).

Pharmacodynamic interactions

Accompanying application of tacrolimus with drugs that have nephro- or neurotoxic effects, increases the risk of neuro- and nephrotoxicity (eg, aminoglycosides, gyrase inhibitors (DNA topoisomerase of the second kind), kormmoxazole, NSAIDs, vancomycin, ganciclovir and acyclovir). Amphotericin B, ibuprofen reinforce risk of development Mr.efrotoxicity of tacrolimus.

Since treatment with tacrolimus may be accompanied by development of Hyperkalemia or increased previous hyperkalemia, should avoid excessive intake of potassium or applications potassium-sparing diuretics (for example, amiloride, triamterene or spironolactoi).

When vaccinating against the background of tacrolmus, the possible reduction in vaccine efficacy should be considered, and avoid the introduction of live attenuated vaccines.

Clinically significant interactions

The following interactions tacrolimus with drugs of concomitant therapy were observed with clinical application. The main mechanism of interaction is known. Almost all patients taking the drugs listed below, marked with an asterisk (*), may need to adjust its dose. Admission tacrolimus and other the following drugs may require dose adjustment in some cases. Preparations, inhibitory isoenzyme CYP3A4 and significantly increase concentration tacrolimus in the blood: keto k azole *, fluconazole *, itraconazole *, voriconazole *; macrolide antibiotics (erythromycin *); inhibitors HIV protease (nelfinavir, saquinavir, rptonavir); hepatitis C protease inhibitors (telaprevir, boceprevir).

Drugs with less pronounced drug interaction: clotrimazole, nifedipine, nicardipine, clarithromycin, josamycin, danazol, ethinylestradiol, omeprazole, blockers of "slow" calcium channels (such as diltiazem); nefazodone, verapamil, amiodarone.

Based on research results in vitro the following substances can be considered as potential andinhibitors metabolism tacrolimus: bromocriptine, cortisone, dapsone, ergotamine, gstoden, lidocaine, mephenytoin, miconazole, midazolam, nilvadipine, porphyridron, quinidine, tamoxpticope, (triacetyl) oleandomycin, norethisterone.

Recommended to avoid the use of grapefruit juice in connection with the possibility of increasing the level of tacrolimus in the blood. Lansoprazole and ciclosporin can potentially inhibit CYP ZA4-mediated metabolism of tacrolimus and increase its concentration in the blood.

Other potential interactions, increasing the systemic exposure of tacrolimus: prokinetic facilities (metoclonamid, qizapride), cimetidine, magnesium hydroxide and aluminum.

Preparations, inhibitory isoenzyme CYP3A4 and the tacrolimus concentration in the blood: rifampicin *; phenytoin *; phenobarbital; St. John's Wort perforated.

Glucocorticosteroids at maintenance doses usually reduce the concentration of tacrolimus in the blood. High doses of prednisolone methyl prednisolone, used to treat acute rejection, may increase or decrease the level of tacrolimus in the blood.

Effect of tacrolimus on the metabolism of other drugs Tacrolimus has a significant effect on the metabolism involving isoenzyme CYP3A4. Thus, Thus, the combined use of tacrolimus with drugs that are metabolized by an isoenzyme CYP3A4, can affect their metabolism (for example, cortisone, testosterone).

Tacrolimus increased the concentration of phenytoins in the blood.

It was shown that the half-life of cyclosporin increased with simultaneous application with tacrolimus. In addition, synergistic / additive nephrotoxic effects. For these reasons not recommended combined application of cyclosporine and tacrolimus, and when administered to patients who previously received ciclosporin, it is necessary follow caution.

As tacrolimus can affect metabolism steroidal contraceptives, special attention should be given to contraception. Data on the interaction of tacrolimus with statins are bordered. Clinical observations suggest that with simultaneous admission from tacrolimus the pharmacokinetics of statins do not change.

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

Preparations, inducing isoenzyme CYP3A: carbamazepine, metamizol sodium and isoniazid.

Special instructions:

AT primary post-transplant period, the following parameters should be regularly monitored: blood pressure, ECG, neurological status and vision, fasting glycemia, electrolyte concentration (especially potassium), hepatic and renal function, hematologic and the agent and, coagulogram, protein concentration in blood plasma. In the presence of clinically relevant changes, a correction immunosuppressive therapy.

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

When using drugs tacrolimus should avoid the appointment of herbal products containing St. John's wort (Hypericum perfircitum), as well as other herbal remedies, which can cause a decrease (change) concentrations tacrolimus in the blood and have an adverse effect on clinical effect of the drug. It is necessary to monitor the concentration of tacrolimus in the blood for the purpose of timely dose adjustment with simultaneous application of tacrolimus from drugs, being strong inhibitors CYP3A4, (eg, telaprevir, boceprevir ritonavir ketoconazole, voriconazole, itraconazole, telithromycin, clarithromycin) or inducers CYP3A4 (eg, rifampicin, rifabutin).

With diarrhea, tacrolimus levels in the blood can change significantly; When diarrhea occurs, a thorough monitoring of concentrations of tacrolimus in the blood.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 hypertrophy of the interventricular septum, reported as cardiomyopathy, were rarely observed in patients, who took tacrolimus. In most cases, myocardial hypertrophy was reversible, was observed primarily in children at concentrations (C₀) tacrolimus in the blood, exceeding recommended. Other factors that increase the risk of this undesirable phenomenon include: availability preceding heart disease, the use of corticosteroids, hypertension, renal and hepatic dysfunction, infection, hypervolemia, edema. Patients who are at high risk and are receiving intensive immunosuppressive therapy, in particular children, before and after transplantation (after 3 and 9-12 months) is necessary spend echocardiographic and ECG monitoring. If are identified anomalies, should be to consider The question of reducing the dose of medicines containing tacrolimus or substituting them for another immunosuppressant.

Patients receiving tacrolimus treatment reported cases of development gastrointestinal perforations, which can lead to life-threatening or severe conditions. If symptoms occur, indicating on gastrointestinal perforation, an adequate treatment should be prescribed.

Tacrolimus may cause lengthening of the interval QT, the development of cardiac rhythm disturbances such as "pirouette" (bidirectional spindle-shaped ventricular tachycardia) is possible. In the treatment of patients with diagnosed congenital syndrome of an elongated interval QT, with the alleged or acquiredth syndrome elongated interval QT, patients receiving drugs, lengthening interval QT, causing electrolyte violations or increasing concentration (exposure) tacrolmus blood, you should be extra careful. 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 insufficiency, bradyarrhythmias and electrolyte disturbances.

Have patients treated tacrolimus, possibly the development of post-transplant lymphoproliferative diseases (PTLZ) associated with the Epstein-Barr virus (VEB). When simultaneous application of Tacrolumnus with antilymphocytic antibodies (for example, daclizumab, basiliximab) risk PTLZ increases. Children under 2 years old, as well as children with a negative test for the capsid antigen of the Einstein-Barr virus are among the group at high risk of developing PTLZ. Therefore, before the appointment of the drug in this group of patients Serological examination 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.

There are reports of the occurrence of the syndrome of reversible posterior encephalopathy with tacrolimus therapy. If the patient receiving tacrolimus, there are symptoms characteristic of the syndrome of reversible posterior encephalopathy: headache, mental disorders, convulsions and visual disturbances, it is necessary to carry out magnetic resonance imaging. When the diagnosis is confirmed, adequate control above arterial pressure and convulsions, and immediately stop systemic administration tacrolimus. In the case of these measures, this condition is completely reversible in most patients.

In patients receiving immunosuppressive therapy, including tacrolimus, the 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 on background immunosuppressive therapy.

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

All patients were noted risk factors for PACAs, such as presence of parvovirus B19 infection, disease or concomitant therapy associated with the possibility of developing a PACA.

Immunosulstemvnaya therapy increases the risk of malignant neoplasms, in particular, malignant tumors of the skin. 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.

Takrolimue 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 the activity of the isoenzyme CYP3A4.

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.

The disorders caused by the drug can be intensified when it is used together with alcohol.

Form release / dosage:

Capsules 0.5 mg, 1 mg, 5 mg.

10 capsules per blister of PVC / PE / PVDC / aluminum. By 5, 6, 9

or 10 blisters are placed in a bag (aluminum / aluminum) containing Desiccant with the inscription: "Not there is! ". For 1 package together with instruction on medical application is placed in cardboard pack.

Packaging:(10) - blisters (10) - aluminum foil bags, two-layer-packs, cardboard
(10) - blisters (5) - aluminum foil bags, double-layered, cardboard boxes
(10) - blisters (5) - bags made of aluminum foil, double-layer-packs, cardboard
(10) - blisters (6) - aluminum foil bags, two-layer-packs, cardboard
(10) - blisters (9) - aluminum foil bags, double-layer, cardboard packs

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Special precautions when destroying an unused preparation

There is no need for special precautions when destroying an unused preparation.

Shelf life:

2 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-001697

Date of registration:04.05.2012

The owner of the registration certificate:Novartis Pharma AGNovartis Pharma AG Switzerland

Manufacturer: & nbsp

SANDOZ PRIVATE, Limited India

Representation: & nbspSANDOZ SANDOZ Switzerland

Information update date: & nbsp02.09.2015

Illustrated instructions

Instructions

Tacrosel® (Takrosel®)