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

Housing: gelatin 83.56%, water 14.50%; sodium lauryl sulfate 0.08%; coloring agent iron oxide yellow (E 172) 0.2331 %; titanium dioxide (E 171) 1.6234 %.

Composition of food inks: shellac 24-27%, anhydrous alcohol 23-26%, isopropanol 1-3%, butanol 1-3%, propylene glycol 3-7%, concentrated ammonia solution 1-2%, iron dye oxide black 24-28%, potassium hydroxide 0,05% -0,1%, purified water 15-18%.

Capsules 1 mg:

Active substance: tacrolimus monohydrate 1.02 mg (equivalent to 1.0 mg tacrolimus, respectively).

Excipients: lactose monohydrate 48.68 mg; croscarmellose sodium 11.14 mg; hypromellose E5 0.96 mg; magnesium stearate 0.62 mg.

Capsule shell composition:

Cap: gelatin q.s. up to 100%, water 14.50 ± 1.5 %; sodium lauryl sulfate 0.08%; titanium dioxide (E 171) 2.1118%.

Housing: gelatin q.s. up to 100,%, water 14.50 ± 1.5 %; sodium lauryl sulfate 0.08 %; titanium dioxide (E 171) 2.1118%.

Capsules 5 mg:

Active substance: tacrolimus monohydrate 5.11 mg (equivalent to 5.0 mg tacrolimus, respectively).

Excipients: lactose monohydrate 99.26 mg; croscarmellose sodium 24.00 mg; hypromellose E5 4.80 mg; magnesium stearate 1.34 mg.

Capsule shell composition:

Cap: gelatin 83.54%, water 14.50 %; sodium lauryl sulfate 0.08%; titanium dioxide (E 171) 1.6088%, iron dye red oxide (E 172) 0.2700%.

Housing: gelatin 83.54 %, water 14.50 %; sodium lauryl sulfate 0.08%; titanium dioxide (E 171) 1.6088%; iron dye red oxide (E 172) 0.2700 %.

Composition of food inks: shellac 24-27%, anhydrous alcohol 23-26%, isopropanol 1-3%, butanol 1-3%, propylene glycol 3-7%, concentrated ammonia solution 1-2%, iron dye oxide black 24-28 %, potassium hydroxide 0.05% -0.1%, purified water 15-18%.

Description:

Capsules 0.5 mg:

Hard gelatin capsules light yellow / light yellow in size "5", on the lid there is an inscription "TCR", and on the body and "0.5" containing a white or almost white granular powder.

Capsules 1 mg:

Hard gelatin capsules white / white in size "5", on the lid there is an inscription "TCR", and on the body "1", containing a white or almost white granular powder;

Capsules 5 mg:

Hard gelatin capsules pink / pink in color "4", on the lid> there is an inscription "TCR", and on the body "5" containing white or almost white granular powder.

Pharmacotherapeutic group:immunosuppressant

Pharmacodynamics:

Immunosuppressant. At the molecular level, the effects of tacrolimus are mediated by binding to the cytosolic protein (FKBP12), which is responsible for intracellular accumulation of the drug. The complex of RKBP12-tacrolimus specifically and competitively binds to calcineurin and inhibits it, which leads to calcium-dependent inhibition of T-cell signaling transduction pathways, thereby preventing transcription of a discrete group of lymphokine genes. Suppresses the formation of cytotoxic lymphocytes, which, in general, are responsible for the rejection of the graft, reducesT-cell activation, T-helper-dependent proliferation of B cells, and the formation of lymphokines (such as interleukins-2, -3 and γ-interferon), the expression of interleukin-2 receptor.

Pharmacokinetics:

Absorption

Tacrolimus is absorbed from the gastrointestinal tract. The maximum concentration (C max) of tacrolimus in the blood is reached after about 1-3 hours. In some patients, the drug is continuously absorbed, for a long timeinside ' time. Average Bioavailability when taking tacrolimus inside is 20% - 25%.

In most cases, after taking the drug inside (0.30 mg / kg / day) after liver transplantation, the equilibrium concentration of tacrolimus was reached within 3 days.

The speed and degree of absorption of tacrolimus is higher when taken on an empty stomach. With the simultaneous use of the drug with food, a decrease in the rate and degree of absorption is noted, which is more pronounced after eating a meal with a moderate fat content. The influence of foods rich in carbohydrates is less pronounced.

In patients with a liver transplant in a stable state, the bioavailability of tacrolimus decreased with ingestion after eating (34% of calories). In addition, there was a decrease in the area under the "concentration-time" curve (AUC) (27%) of the maximum concentration of Cmax (50%) and an increase in time, until the maximum concentration (tmax) (173%) in whole blood.

In patients with a kidney transplant in a stable state, the effect of food intake on the bioavailability of the drug was less pronounced. There was a decrease AUC (2-12%) and Cmax (15-38%) and an increase tmax (38 - 80%) in whole blood.

Isolation of bile does not affect the absorption of tacrolimus.

A strong correlation between AUC and the minimum concentrations of the drug in whole blood upon reaching the equilibrium state, in connection with which the control of tacrolimus concentration in the blood can serve for an objective evaluation of its systemic action;

Distribution and deduction

In the human body, the distribution of tacrolimus after intravenous (IV) administration of the drug is biphasic.

The drug is largely associated with erythrocytes, so the distribution coefficient in whole blood. Plasma concentrations are approximately 20: 1. In the blood plasma tacrolimus binds well to proteins (> 98.8%), mainly with serum albumin and α-1-glycoprotein.

Tacrolimus is widely distributed in the body. The equilibrium volume of distribution, based on the concentration in the blood plasma, is approximately 1300 liters (healthy volunteers), and in whole blood - 47.6 liters.

Tacrolimus is a drug with a low level of clearance. In healthy volunteers, the average total clearance calculated on the basis of the concentration of the drug 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 l / h and 3.9 l / h, respectively.In children with liver transplant, the total clearance value is approximately twice as high as in adult patients with a liver transplant. The higher clearance observed after transplantation is probably due to factors such as low hematocrit andhypoproteinemia, which leads to an increase in the free fraction of tacrolimus, or. the same increase in metabolism against a background of high doses of glucocorticosteroids.

The period of 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 a liver transplant, the half-life is on average 11.7 hours and 12.4 hours, respectively, compared to 15.6 hours in adult patients with kidney transplant.

Metabolism

Tacrolimus is actively metabolized in the liver, mainly with the involvement of hepatic microsomal cytochrome P450-ZA4 (isoenzyme CYP3A4). In addition, the metabolism of tacrolimus occurs in the wall of the intestine. Several metabolites of the drug have been identified, among which only one - has significant immunosuppressive activity in conditions in vitro equivalent tacrolimus. Other metabolites have very weak immunosuppressive activity. In the systemic blood stream, only one inactive metabolite is detected in low concentrations. Consequently, metabolites do not play a role in the formation of pharmacological activity of tacrolimus.

Excretion

After intravenous administration and oral administration of tacrolimus labeled ¹⁴With an isotope, most radiolabeled drug is excreted through the intestine. Approximately 2% is excreted by the kidneys. Less 1% unchanged tacrolimus was found in urine and feces, therefore, tacrolimus almost completely metabolized before excretion from the body.

The main way of elimination is bile.

Indications:

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

- Treatment of allograft rejection in the development of resistance to other immunosuppressive drugs.

Contraindications:

Hypersensitivity to tacrolimus or other macrolides.

Hypersensitivity to any components of the drug.

Pregnancy and lactation:

The results of preclinical studies and studies conducted in humans show that the drug can penetrate the placenta.Safety of application of tacrolimus in pregnant women is not established, therefore, one should not prescribe it pregnant, except when the received benefit from treatment for the mother justifies the potential risk to the fetus. When using the drug in utero should monitor the condition of the newborn to identify possible side effects of tacrolimus (in particular, nephrotoxicity).There is a risk of premature birth (<37 weeks), the development of hyperkalemia in the newborn, which, however, spontaneously corrected. Pelactation

Clinical studies have shown that tacrolimus excreted in breast milk. If it is necessary to prescribe the drug during lactation, breastfeeding should be stopped, since the undesirable effects of the drug on the baby's organism can not be ruled out.

Dosing and Administration:

The choice of tacrolimus dose should be based on a clinical assessment of the rejection and tolerability response, in each patient individually, and also taking into account monitoring the concentration of the drug in the blood (below are the permissible ranges of drug concentrations in the blood).In case of development of clinical signs of rejection should consider changing immunosuppressive therapy.

In most cases To begin treatment it is possible with appointment tacrolimus inside; If necessary, it is allowed to dissolve the contents of the capsule in water and inject it through a nasogastric tube.

Usually the drug is administered in combination with other immunosuppressive drugs in the postoperative period. Dose; tacrolimus can change in depending on the selected treatment regimen.

The daily dose for oral intake is recommended to be divided into two doses - in the morning and in the evening. The capsule should be used immediately after removal from the blister pack.

The capsule must be swallowed with a liquid (preferably water).

Usually capsules are taken on an empty stomach, or 1 hour before or 2-3 hours after eating, which allows achieving maximum absorption of the drug.

To suppress the reaction of transplant rejection, immunosuppressive therapy should be carried out for a long time so the period of taking the drug is not limited.

Recommended dosing regimens

Liver transplantation

Prevention of transplant rejection in adults. The recommended initial dose of tacrolimus is 0.10 - 0.20 mg / kg / day orally in two divided doses (morning and evening). The drug should be started approximately 12 hours after the operation is completed.

If it is not possible to prescribe the medication internally due to the patient's severe condition after the operation, intravenous drip administration of the drug at a dose of 0.01-0.05 mg / kg / day for 24 hours should be started.

Prevention of transplant rejection in children.

The recommended initial dose of tacrolimus is> 0.30 mg / kg / day orally in two reception (morning and evening). If there is no way to prescribe the drug. In view of the patient's severe condition after the operation, intravenous drip administration of the drug at a dose of 0.05 mg / kg / day for 24 hours should be started.

Correction of dose in the postoperative period the adults and children.

In the postoperative period, the dose of the drug is usually lowered. In some cases, cancellation of concomitant immunosuppressive therapy and management of a patient with Tacrolimus-Teva monotherapy is allowed. Improvement of the patient's condition after transplantation may affect the pharmacokinetics of tacrolimus, which necessitates correction of the dose of the drug.

Treatment of rejection the adults and children.

To treat transplant rejection, higher doses of Tacrolimus-Teva should be used in combination with glucocorticosteroids and short courses of mono / polyclonal antibodies. If signs of toxicity appear, you may need to reduce the dose of Tacrolimus-Teva.

Kidney Transplantation

Prophylaxis of graft rejection in adults

The recommended initial dose of tacrolimus is 0.20 - 0.30 mg / kg / day in two - intake (morning and evening). The drug should be started within 24 hours after the operation is completed.

If it is not possible to prescribe the medication internally due to the patient's severe condition after the operation, intravenous drip administration of the drug at a dose of 0.05 -0.10 mg / kg / day for 24 hours should be started.

Prophylaxis of transplant rejection in children

The recommended initial dose of tacrolimus is 0.30 mg / kg / day at two doses (morning and evening). If it is not possible to prescribe the medication internally due to the patient's severe condition after the operation, intravenous drip administration of the drug at a dose of 0.075-0.100 mg / kg / day for 24 hours should be started.

Correction of dose in the postoperative period in adults and children

In the postoperative period, the dose of Tacrolimus-Teva is usually reduced. In some cases, cancellation of concomitant immunosuppressive therapy, and, patient management of Tacrolimus-Teva monotherapy, is permitted. Improvement of the patient's condition after transplantation may affect the pharmacokinetics of tacrolimus, which necessitates correction of the dose of the drug.

To achieve a similar concentration of the drug in the blood, children usually need doses (in terms of body weight) 1.5-2 times higher than for adults.

Treatment of rejection in adults and children

To treat graft rejection, an increase in the dose of Tacrolimus-Teva in combination from additional appointment of glucocorticosteroid therapy and shortcourses of mono- or polyclonal antibodies. In case of signs of toxicity (see section Side effect) the dose of the drug should be reduced.

When switching to Tacrolimus-Teva, treatment starts with the dose recommended for initial immunosuppression.

Recommendations for the transfer of patients from cyclosporine to tacrolimus are set out in the section "Correction of the dose of the drug in special clinical cases. "

Heart transplantation.

Prophylaxis of graft rejection in adults

Tacrolimus-Teva may be administered against a background of mono / polyclonal antibodies (which allows delaying therapy with Tacrolimus-Teva) or in a clinically stable patient without the introduction of mono / polyclonal antibodies.

After the introduction of mono / polyclonal antibodies, the recommended dose of the drug is 0.075 mg / kg / day orally in two divided doses (morning and evening). The first dose of the drug should be prescribed within 5 days after the operation is completed, as soon as the patient's condition is stabilized. If it is not possible to prescribe the medication internally due to the patient's severe condition after surgery, an intravenous drip of the drug at a dose of 0.01-0.02 mg / kg / day for 24 hours is possible.

As an alternative regimen for patients without symptoms of impaired liver function, kidney function tacrolimus may be administered orally within 12 hours after transplantation. In this case, the initial dose of tacrolimus is 2 to 4 mg / day in combination with mycophenolate mofetil and glucocorticosteroids, or in combination with sirolimus and glucocorticosteroids.

Prophylaxis of transplant rejection in children

After heart transplantation in children, Tacrolimus-Richter is used both in combination with and without the inducers of antibodies.

Without the appointment of antibody inducers, the recommended initial dose of tacrolimus for intravenous drip infusion is 0.03-0.05 mg / kg / day for 24 hours, which allows a tacrolimus concentration of 15 to 25 ng / ml in blood to be achieved. If the clinical the patient's condition allows him to take the drugs inside it is recommended to transfer the patient to taking tacrolimus in capsules. The initial dose of the drug for oral administration is 0.30 mg / kg / day and can be given after 8 - 12 hours after completion of intravenous infusion of tacrolimus.

After the induction of antibodies, the recommended dose of Tacrolimus-Teva is 0.10-0.30 mg / kg / day orally in two divided doses (morning and evening).

Correction of dose at postoperative period the adults and children

In the postoperative period, the dose of Tacrolimus-Teva is usually reduced.

Improvement of the patient's condition after transplantation can have an impact on pharmacokinetics of tacrolimus, which entails the need to adjust the dose of the drug.

Treatment of rejection in adults and children

To treat graft rejection, a dose of the drug Tacrolimus-Teva in combination with an additional appointment of glucocorticosteroid therapy and short, courses of mono- or polyclonal antibodies

Have of adults in the transition to Tacrolimus-Teva, the initial dose is 0.15 mg / kg / day in two divided doses (morning and evening).

At children at transition to a preparation Tacrolimus-Richter initial dose is 0.20 - 0.30 mg / kg / day in two divided doses (morning and evening).

Recommendations for the transfer of patients from cyclosporine to tacrolimus are set out in the section "Correction of the dose of the drug in special clinical cases. "

Treatment of rejection, other transplants

Recommended doses for lung, pancreatic and intestinal transplantation are based on very limited data from prospective clinical trials. At lung transplantation, the initial dose of Tacrolimus-Teva was 0.10 g 0.15 mg / kg / day orally, 0.2 mg / kg / day for pancreas transplantation and 0.3 mg / kg / day for gut transplantation inside.

Correction of the dose of the drug in special clinical cases

Patients with hepatic impairment

Patients with severe impairment of liver function may need to reduce the dose of the drug in order to maintain the concentration of the drug in the blood in the recommended range.

Patients with impaired renal function

Since the pharmacokinetics of tacrolimus does not depend on the function of the kidneys, correction of the dose in such cases is not required. However, given the presence of nephrotoxic action in tacrolimus, it is recommended to carefully monitor the kidney function (including the concentration of serum creatinine, creatinine clearance and diuresis).

Elderly

At present, there are no data on the need to correct the dose of the drug in the elderly.

Transfer of patients with cyclosporine therapy

Care should be taken when transferring patients from cyclosporine to Tacrolimus-Teva. Admission tacrolimus can begin after the determination of the concentration of cyclosporine in the blood and clinical assessment of the patient's condition. In case of an increased concentration of cyclosporine in the blood, taking Tacrolimus-Richter should be postponed. In practice, tacrolimus treatment begins 12 to 24 hours after cyclosporine withdrawal.Therapy should begin with the initial oral dose recommended for primary immunosuppression in a specific allograft (both in adult patients and in children). After transferring the patient to tacrolimus it is necessary to monitor the concentration of cyclosporine in the blood, as it is possible to disrupt the clearance of cyclosporine.

Recommendations for maintaining the required concentration of the drug in whole blood

The choice of dose should be based on. clinical evaluation of rejection and tolerability in each patient individually.

In the postoperative period, it is necessary to monitor the concentration of tacrolimus in the blood. When taking the drug inside the test to determine the concentration of tacrolimus, you need to get blood samples through12 hours after taking the drug, immediately before taking the next dose. The frequency of monitoring the concentration of the drug in the blood depends on the clinical situation. Since Tacrolimus-Teva is a drug with a low level of clearance, correction of the dosing regimen can take several days, when changes in drug concentrations in the blood will become apparent.In the early posttransplant period, drug concentrations in the blood should be monitored approximately twice a week. In addition, the concentration of tacrolimus in the blood should be monitored after correcting the dose of the drug, changing the regime of immunosuppressive therapy, or after a combined intake with drugs that can affect the concentration of tacrolimus in the blood. The results of clinical studies allow us to assume that most patients can successfully undergo treatment if the concentration of tacrolimus is maintained at a level below 20 ng / ml. When evaluating the results of the analysis, it is important to consider the clinical state of the patient.

In clinical practice in the early posttransplant period, the concentration of the drug in whole blood ranged from 5 to 20 ng / ml in patients after liver transplantation and from 10 to 20 ng / ml in patients after kidney and heart transplantation. Subsequently, during the course of maintenance therapy, the concentration of the drug in the blood is usually 5-15 ng / ml after any of these operations (liver, kidney and heart transplantation).

Side effects:

Many of the following adverse reactions are reversible and / or reduced with a lower dose of the drug. When using the drug inside the incidence of adverse reactions is lower than with intravenous administration. Adverse reactions are given in descending order of frequency: very often (> 1/10); often (> 1/100, <1/10); infrequently (> 1/1000, <1/100); rarely (> 1/10000, <1/1000); very rarely (<1/10000 /, including isolated cases).

From the side of the cardiovascular system

very often: arterial hypertension;

often: ischemic heart disease, tachycardia; thromboembolic and ischemic manifestations, bleeding, peripheral vascular disorders, decreased vascular tone;

infrequent: heart rhythm disturbances and conduction, cardiac arrest, heart failure, cardiomyopathy, ventricular myocardial hypertrophy, palpitations, abnormalities in ECG parameters, pulse deficit; myocardial infarction, deep vein thrombosis of the extremities, shock;

rarely: effusion into the pericardial cavity;

very rarely: abnormalities in echocardiography.

On the part of the hematopoiesis system

often: anemia, leukopenia, thrombocytopenia, leukocytosis, erythrocyte pathology; infrequently: coagulopathy, abnormalities in the parameters of the coagulation system, pancytopenia, neutropenia;

rarely: thrombocytopenic purpura, hypoprothrombinemia.

From the gastrointestinal tract

very often: diarrhea, nausea;

often: inflammatory diseases of the gastrointestinal tract, gastrointestinal - ulcers and perforations, gastrointestinal bleeding, stomatitis, ulceration of the oral mucosa, ascites, vomiting, abdominal pain, indigestion, abdominal discomfort, constipation, flatulence, bloating abdomen, loose stools; infrequent: intestinal obstruction, peritonitis, acute and chronic / pancreatitis, increased activity of blood amylase; gastroesophageal reflux disease, a violation of the evacuation function of the stomach; rarely: subileus, pseudocyst of the pancreas.

From the hepatobiliary system

often: violations of activity - liver enzymes, cholestasis and jaundice, disruption of hepatocyte integrity and hepatitis, cholangitis;

rarely: thrombosis of the hepatic artery, thrombosis of the veins of the liver;

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

Infections and invasions

In patients receiving tacrolimus, as in the treatment with other immunosuppressive drugs, the risk of developing infectious diseases (viral, bacterial, fungal or protozoal etiology) is increased.It is also possible to worsen the course of previously diagnosed infectious diseases, generalization or localization of the infectious process.

Benign, malignant and unclassified neoplasms Patients receiving immunosuppressive drugs are part of the group at increased risk of developing malignant neoplasms. Against the background of application tacrolimus reported the development of benign and malignant tumors, including the development of the virus Epstein-Barr-associated (EBV) lymphoproliferative diseases and skin cancer.

Allergic reactions

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

Co hand endocrine system rarely: hirsutism

Metabolic and nutritional disorders

very often: hyperglycemia, diabetes, hyperkalemia;

often: hypomagnesemia, hypophosphatemia, hypokalemia, hypocalcemia, hyponatremia, hypervolemia, hyperuricemia, decreased appetite, anorexia, metabolic acidosis, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, other disturbances of water-electrolyte balance;

infrequently: dehydration, hypoproteinemia, hyperphosphatemia, hypoglycemia.

Mental disorders

very often: insomnia;

often: agitation, confusion and disorientation, depression, mood disorders, nightmares, hallucinations, mental disorders; infrequently: psychopathy.

From the central nervous system very often: tremor, headache;

often: epileptoid seizures, impaired consciousness, paresthesia and dysesthesia, peripheral neuropathy, dizziness, writing disorders, disorders of the nervous system;

infrequently: coma, cerebral hemorrhage, strokes, paralysis and paresis, encephalopathy, speech disorders, amnesia;

rarely: hypertension;

very rarely: myasthenia gravis.

From the side of the organ of vision

often: blurred vision, photophobia, eye diseases;

infrequently: cataract;

rarely: blindness.

From the side of the organ of hearing and balance

often: tinnitus;

infrequently: hearing loss;

rarely: sensorineal deafness;

very rarely: hearing impairment.

On the part of the respiratory system.

often: dyspnea, diffuse parenchymal lung diseases, pleural effusion, pharyngitis, cough, nasal congestion, rhinitis;

infrequently: respiratory failure, respiratory tract disorders, bronchial asthma;

rarely: acute respiratory distress syndrome.

From the skin and subcutaneous fat often: itching, rash, alopecia, acne, excessive sweating; infrequently: dermatitis, photosensitivity;

rarely: toxic epidermal necrolysis (Lyell's syndrome); very rarely: Stevens-Johnson syndrome.

Co hand musculoskeletal system and connective tissue

often: arthralgia, convulsions, pain in the limbs, back pain;

infrequently: joint disease.

From the side of the kidneys and urinary tract

very often: impaired renal function;

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

infrequently: anuria, hemolytic-uremic syndrome;

very rarely: nephropathy, hemorrhagic cystitis.

Co hand reproductive system

infrequently: dysmenorrhea and uterine bleeding.

General disorders and reactions at the site of administration

often: asthenia, fever, edema, pain and discomfort, increased alkaline phosphatase activity, weight gain, violation of temperature sensitivity;

infrequently: multiorgan insufficiency, influenza-like, temperature fluctuations, pressure behind the sternum, feeling - fear, anxiety, discomfort, increased lactate dehydrogenase (LDH) activity in the blood, weight loss;

rarely: thirst, falling, shortness of breath, a decrease in motor activity, ulcers;

very rarely: hypertrophy of adipose tissue.

Injuries, poisoning and complications of medical manipulations

often: primary transplant dysfunction.

Overdose:

Data on the overdose of tacrolimus are very limited. There are only isolated reports of a random overdose of the drug, with the following symptoms: tremor, headache, nausea and vomiting, infectious complications, urticaria, lethargy, increased blood urea nitrogen and creatinine, as well as increased ALT activity.

There is no specific antidote to Tacrolimus-Teva. In case of an overdose, general supportive and symptomatic therapy is prescribed.

Given the high molecular weight, poor solubility in water and the formation of strong bonds with erythrocytes and plasma proteins, it can be assumed that tacrolimus Do not undergo dialysis.In some patients with a very high concentration of the drug in the blood plasma, hemofiltration made it possible to reduce its toxic concentration. In case of development of intoxication after taking the drug inside, it is necessary to perform gastric lavage and / or prescribe adsorbents (Activated carbon) as soon as possible after taking the drug.

Interaction:

Metabolic interaction

Metabolism of tacrolimus occurs in the liver with the participation of an isoenzyme CYP3A4. In addition, there are indications of the presence, metabolism in the intestinal wall with the participation of the isoenzyme CYP3A4. Combined use with medicinal or herbal preparations inhibiting or inducing isoenzyme CYP3A4 can affect the metabolism of tacrolimus, which leads to an increase or decrease in its concentration
in blood. Therefore, with the appointment of tacrolimus with drugs that are
metabolized by isoenzyme CYP3A4 dependent pathways, it is recommended to monitor the concentration of tacrolimus in the blood and adjust its dose to maintain the necessary clinical effect of the drug.

Inhibitors of Metabolism

The following substances increased the concentration of tacrolimus in the blood.

Expressed - the interaction was noted with, antifungal drugs:

- ketoconazole, fluconazole, itraconazole and voriconazole;

- antibiotics of the macrolide group: erythromycin; or HIV protease inhibitors (ritonavir).

The combined administration of these drugs may require a reduction in the tacrolimus dose in virtually all patients.

Less pronounced interaction was noted with the following drugs: clotrimazole, clarithromycin, josamycin,nifedipine, nicardipine, diltiazem, verapamil, danazol, ethinyl estradiol, omeprazole and nefazodone.

In conditions in vitro following drugs showed a pronounced inhibitory effect on metabolismtacrolimus: bromocriptine, cortisone, dapsone, ergotamine, gestodene, lidocaine, mephenytoin, miconazole, midazolam, nilvadipine, norethisterone, quinidine, tamoxifen, troleandomycin.

Grapefruit juice will concentrate the concentration of tacrolimus in the blood, therefore it should not be used in combination with taking tacrolimus.

Inductors metabolism

The following substances reduced the concentration of tacrolimus in the blood.

The pronounced interaction was noted with the following preparations: rifampicin, phenytoin or extract of St. John's wort perfumed (Hypericum perforatum), on the background of which it may be necessary to increase the dose of tacrolimus in practically all patients. Clinically pronounced interaction was noted with phenobarbital. It was shown that maintenance doses of glucocorticosteroids reduce the concentration of blood tacrolimus.

High doses of prednisolone or methylprednisolone, used in connection with the transplant rejection reaction, can increase the concentration of tacrolimus in the blood. Carbamazepine, metamizole and isoniazid can reduce the concentration of tacrolimus in the blood.

Effect of tacrolimus on metabolism other medicines

It is known that tacrolimus inhibits isoenzyme CYP3A4, therefore, the combined use of it with drugs whose metabolism occurs with the participation of an isoenzyme - CYP3A4, can alter the metabolism of these drugs.

The half-life of cyclosporine on the background of taking tacrolimus is prolonged. In addition, the development of synergistic / additive nephrotoxic effects is possible. For this reason, simultaneous administration of cyclosporine and tacrolimus is contraindicated, and when transferring patients from cyclosporine to tacrolimus Care should be taken.

It was shown that tacrolimus increases the concentration of phenytoin in the blood.

As tacrolimus is able to reduce the clearance of steroid contraceptives, which increases the exposure of hormones, then special attention should be paid to the issue of contraceptive measures during treatment.

Information about the interaction. between tacrolimus and statins are very limited. The available data indicate that tacrolimus has virtually no effect on the pharmacokinetics of statins.

The results of studies in animals showed thattacrolimus is able to reduce clearance and increase the half-life of phenobarbital and antipyrine.

Other types of interactions that lead to clinically pronounced effects.

The combined use of tacrolimus with nephrotoxic or neurotoxic drugs may contribute to the enhancement of the toxic properties of drugs (aminoglycosides, gyrase inhibitors, vancomycin, sulphometoxazole + trimethoprim, non-steroidal anti-inflammatory drugs (NSAIDs), ganciclovir or acyclovir).

Increased nephrotoxicity was noted after the appointment of amphotericin B and ibuprofen in combination with tacrolimus.

Since - taking tacrolimus can lead to the development orexacerbation of hyperkalemia, should avoid the appointment of potassium-sparing diuretics (amiloride, triamterene or spironolactone).

Immunosuppressive drugs can have a negative effect on the effectiveness of vaccination. The appointment of live vaccines should be avoided.

Binding to blood plasma proteins

Tacrolimus binds to a high degree with the proteins of plasma, blood. maybecompetitive interaction with drugs with high affinity for plasma proteins (NSAIDs, oral anticoagulants or hypoglycemic agents). Influence on the ability to drive and work with machinery Tacrolimus can cause visual and neurological disorders, which are amplified by joint intake with alcohol.

Special instructions:

In the early postoperative period, the following parameters should be monitored: blood pressure, ECG, neurological and ophthalmologic status, fasting blood glucose, electrolytes (in particular, potassium), liver and kidney function,parameters of clinical blood analysis, indicators of the coagulation system and determination of blood plasma proteins. In case of detection of clinically significant changes, the issue of changing the regimen / intake of immunosuppressive drugs should be considered.

It is necessary to avoid the joint administration of Tacrolimus-Teva with herbal preparations, in particular, with preparations of St. John's wort perfumed (Hypericum perforatum), since there is a high risk of cross-interaction, which can lead to a decrease in tacrolimus concentration in the blood and a decrease effectiveness of the drug.

Since the concentration of tacrolimus in the blood can change significantly with the development of diarrhea, then in this case, a more careful observation of the concentration of tacrolimus is necessary.

Simultaneous administration of cyclosporine and tacrolimus should be avoided, and caution should be exercised in prescribing tacrolimus to patients who have previously received ciclosporin.

There are isolated reports of the development of ventricular hypertrophy and interventricular septum, recorded as cardiomyopathy. In most cases, these phenomena were reversible and were observed, mainly, in children with a tacrolimus concentration in the blood significantly exceeding the recommended level.

Other risk factors include: history of the cardiovascular system, administration of glucocorticosteroids, arterial hypertension, renal or hepatic insufficiency, infectious diseases, hypervolemia and swelling. Thus, the risk group includes children, and patients who receive immunosuppressive therapy for a long time in high doses for a long time. These patients should be carefully observed; Regularly conduct ultrasound of the heart, ECG both before and after transplantation. In case of development and detection of changes, consideration should be given to reducing the dose of Tacrolimus-Teva or switching to another immunosuppressive drug. Tacrolimus-Teva is able to extend the interval- QT, but has a weak potential in the development of a bi-directional spindle-ventricular tachycardia (Torsades de Pointes). When the drug is prescribed for patients with congenital syndrome of an elongated interval QT Care should be taken. In patients taking tarolimus, there was a development of lymphoproliferative diseases associated with the Epstein-Barr virus " (EBV). Patients taking Tacrolimus-Richter should not be prescribed antilymphocytic drugs.In young children (up to two years), EBV-VCA-negative children there was an increased risk of developing lymphoproliferative diseases. Therefore, patients of this group before the reception. Tacrolimus-Teva should be serodiagnostic on EBV-VCA. During treatment it is recommended to perform PCR diagnostics of EBV. Positive polymerase chain reaction (PCR) can - persist for several months and itself, by itself, does not indicate the presence of lymphoproliferative disease or lymphoma.

As with other immunosuppressive drugs, due to the high risk of developing malignant skin tumors, the patient should be contacted with UV radiation sources and sunlight: long-sleeved clothing, sunglasses and hats are recommended.

As with other immunosuppressive drugs, the risk of developing a secondary cancer is not defined.

Have patients with lactase deficiency, lactose intolerance, glucose galactose malabsorption, the drug should be used with caution (in the drug form of the drug contains lactose).

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

Form release / dosage:

Capsules, 0.5 mg; 1.0 mg and 5.0 mg

10 capsules in a blister from Al / Al.

By 3, 5, 6 and 10 blisters in a pack of cardboard along with instructions for medical use.

Packaging:(10) - 10 capsules per blister from Al / Al. (10) / 10 capsules per blister from Al / Al. 10 blisters per pack of cardboard along with instructions for medical use. / - 10 blisters per pack of cardboard along with instructions for medical use.
(10) - 10 capsules per blister from Al / Al. (3) / 10 capsules per blister from Al / Al. For 3 blisters per pack of cardboard along with instructions for medical use. / - 3 blisters per pack of cardboard along with instructions for medical use.
(10) - 10 capsules per blister from Al / Al. (5) / 10 capsules per blister from Al / Al. For 5 blisters in a pack of cardboard along with instructions for medical use. / - 5 blisters per pack of cardboard along with instructions for medical use.
(10) - 10 capsules per blister from Al / Al. (6) / 10 capsules per blister from Al / Al. For 6 blisters in a pack of cardboard along with instructions for medical use. / - 6 blisters per pack of cardboard along with instructions for medical use.

Storage conditions:

Store at a temperature not exceeding 30 ° C.

Keep out of the reach of children!

Shelf life:

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

Terms of leave from pharmacies:On prescription

Registration number:PL-000584

Date of registration:16.09.2011

The owner of the registration certificate:Teva Pharmaceutical Enterprises Co., Ltd.Teva Pharmaceutical Enterprises Co., Ltd. Israel

Manufacturer: & nbsp

INTAS PHARMACEUTICALS, Ltd. India

Representation: & nbspTeva Teva Israel

Information update date: & nbsp02.09.2015

Illustrated instructions

Instructions

Tacrolimus-Teva (Tacrolimus-Teva)