Prograf - instructions for use, doses, side effects, contraindications

At the molecular level, effects and intracellular cumulation of tacrolimus are due to binding to the cytosolic protein (FKBP 12). Complex FKBP 12-tacrolimus specifically and competitively inhibits calcineurin by providing calcium-dependent blocking of T-cell signaling pathways and preventing transcription of a discrete series of lymphokine genes.

Tacrolimus is a highly active immunosuppressant. In experiments in vitro and in vivo tacrolimus clearly reduced the formation of cytotoxic lymphocytes, which play a key role in the transplant rejection reaction. Tacrolimus inhibits the formation of lymphokines (interleukin -2, -3, y-interferon), T cell activation, interleukin-2 receptor expression, and T-helper dependent proliferation of B cells.

Pharmacokinetics:

Distribution and elimination

In the systemic circulation tacrolimus it binds well to erythrocytes. The ratio of tacrolimus concentrations in whole blood and plasma is ~ 20: 1.A significant proportion of tacrolimus in plasma (> 98.8%) is associated with plasma proteins (serum albumin, α-1-acid glycoprotein).

Tacrolimus is widely distributed in the body. The steady-state volume of distribution, taking into account the concentrations in the plasma, is about 1,300 liters (in healthy people). The same index, calculated on whole blood, is on average 47.6 liters.

Tacrolimus is a substance with low clearance. In healthy people, the average overall clearance calculated for concentrations in whole blood is 2.25 l / h. In adult patients, after a liver, kidney and heart transplant, the clearance values were 4.1 liters / hour, 6.7 liters / hour and 3.9 liters / hour, respectively. In children with grafted liver, the total clearance is about 2 times higher than in adult patients with transplanted liver. Low hematocrit and hypoproteinemia contribute to an increase in the unbound fraction of tacrolimus, accelerating the clearance of tacrolimus. Corticosteroids used in transplantation can also increase the intensity of metabolism and accelerate the clearance of tacrolimus.

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

Metabolism and biotransformation

Tacrolimus is actively metabolized in the liver, mainly by cytochrome P450 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 of the drug is practically independent of metabolites.

Excretion

After oral administration ¹⁴C-labeled tacrolimus, most of the radioactivity was found in feces, about 2% in urine, while about 1% of tacrolimus was determined unchanged. Consequently, tacrolimus before elimination almost completely metabolized, the main way of elimination was bile.

Indications:

Prevention of rejection of liver, kidney or heart allograft.

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

Contraindications:

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

Pregnancy and lactation:

Pregnancy

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

Lactation period

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

Dosing and Administration:

Therapy with Prograf® requires careful monitoring by personnel with the appropriate qualifications and with the necessary equipment at their disposal. Prescribe this drug or make changes in immunosuppressive therapy only by physicians with experience of conducting immunosuppressive therapy in patients with transplanted organs.

General Provisions

The initial doses presented below should only be considered as recommendations. In the initial postoperative period, Prograf® is usually used in combination with other immunosuppressants. The dose may vary depending on the regimen of immunosuppressive therapy. The choice of the dose of Prograf® should be based, first of all, on the clinical assessment of the risk of rejection and individual drug tolerance, as well as on the monitoring of tacrolimus concentration in the blood (cf.below is the section "Recommendations for monitoring the therapeutic concentration of tacrolimus in the blood").

When there are clinical signs of rejection, consideration should be given to the need for correcting the regimen of immunosuppressive therapy.

Prograf® can be used either orally or intravenously. In most cases, the drug is administered orally; If necessary, the contents of the capsules can be mixed with water and injected through a nasogastric tube.

Dosing and Administration

Prograf® in a dosage form concentrate for the preparation of a solution for intravenous administration (infusion) is administered only after dilution with 5% dextrose solution or 0.9 % solution of sodium chloride. Use only clear and colorless solutions. Do not administer the drug undiluted. The drug is used only as an intravenous infusion solution. You can not combine Program's solution with other drugs with an alkaline medium (for example, acyclovir and ganciclovir), as tacrolimus is unstable in an alkaline medium. Syringes, needles, bottles, other tools and equipment,used for the preparation and administration of the infusion solution, can be made of polyethylene, polypropylene or glass, but should not contain polyvinyl chloride.

It is not recommended to spray the preparation.

The concentration of the solution after dilution should be between 0.004 and 0.100 mg / ml. The total infusion volume should be 20-500 ml. Infusion is introduced within 24 hours. Unused concentrate for infusion in an open ampoule or unused reconstituted solution for infusions must be discarded to avoid contamination (microbial contamination).

Duration of the drug

The drug is administered parenterally in the event that the patient's condition does not allow him to take Progra's capsules. As soon as the patient's clinical condition improves, it is transferred to oral administration of the preparation in the form of Program capsules.

The duration of intravenous therapy should not last more than 7 days.

After transferring the patient from the parenteral to the oral administration as capsules of tacrolimus, it should be borne in mind that in practice there have been errors in the use of tacrolimus preparations.Errors included 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 dosage regimen should only be carried out under the supervision of a transplant specialist.

Liver transplantation Primary immunosuppression - adults

Intravenous therapy with the drug Prograf is prescribed if the patient's condition does not allow taking the drug in the form of capsules. The initial dose is 0.01-0.05 mg / kg / day, injecting the drug as a continuous 24-hour infusion. When the patient's condition is improved, they are transferred to Prograf® capsules for therapy.

Oral therapy with Prograf® should be started at a dose of 0.10-0.20 mg / kg / day, divided into two doses (for example, in the morning and in the evening).If the patient's condition allows taking the drug inside, the drug should be started approximately 12 hours after the operation is completed.

Primary immunosuppression is children

Intravenous therapy with the drug Prograf is prescribed if the patient's condition does not allow taking the drug in the form of capsules. The initial dose is 0.05 mg / kg / day, injecting the drug as a continuous 24-hour infusion. When the patient's condition is improved, they are transferred to Prograf® capsules for therapy.

The initial dose of the drug for oral administration of 0.30 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 at a dose of 0.05 mg / kg / day as a continuous 24-hour infusion.

Kidney Transplantation

Primary immunosuppression - adults

The drug should be started within 24 hours after the operation is completed. If the patient's condition does not allow taking the medication internally, intravenous therapy should be started from a dose of 0.05-0.10 mg / kg / day as a continuous 24-hour infusion.

When the patient's condition is improved, they are transferred to Prograf® capsules for therapy.Oral therapy with Prograf® should be started at a dose of 0.20-0.30 mg / kg / day, divided into two doses (eg, in the morning and in the evening).

Primary immunosuppression is children

If the patient's clinical condition does not allow him to take the drug inside, intravenous therapy should be started from a dose of 0.075-0.100 mg / kg / day as an intravenous infusion within 24 hours.

When the patient's condition is improved, they are transferred to Prograf® capsules for therapy. The initial dose of the drug for oral administration of 0.30 mg / kg / day should be divided into two doses (for example, in the morning and in the evening).

Treatment of rejection reaction - adults and children

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

When transferring patients to Prograf treatment, the same initial doses are recommended, as with primary immunosuppression. Information on the transfer of patients with cyclosporine therapy to Prograf® is given at the end of the section on "Correction of the dose of the drug in special patient populations."

Heart transplantation

Primary immunosuppression - adults

Prograf® can be used in combination with induction therapy with antibodies (which allows delaying the onset of the use of PROGRAF®) or without the appointment of antibodies in clinically stable patients. Following the induction of antibodies, oral therapy with Prograf® should be started at a dose of 0.075 mg / kg / day divided into two doses (eg morning and evening). Start taking the drug should be within 5 days after the operation, as soon as the patient's clinical condition is stabilized. If the patient's condition does not allow taking the medication internally, intravenous therapy should be started 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 corticosteroids or sirolimus and corticosteroids.

Primary immunosuppression is children

After heart transplantation in children, primary immunosuppression with Prograf® can be carried out both in combination with antibody induction, and independently.In cases where induction is not performed with antibodies and Program® 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 of Prograf® should be 0.30 mg / kg / day and be administered 8-12 hours after discontinuation of intravenous infusion.

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

Treatment of rejection reaction - adults and children

Supportive therapy - adults and children

In the course of maintenance therapy, the doses of Prograf® 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 higher doses of Prograf® in combination with additional corticosteroid therapy and short courses of mono / polyclonal antibodies.

When transferring adult patients to Program® therapy, the initial dose for oral administration of the drug 0.15 mg / kg / day should be divided into two doses (for example, in the morning and in the evening).

When transferring children to Prograf® therapy, the initial dose for oral administration of the drug 0.2-0.3 mg / kg / day should also be divided into two doses (eg morning and evening).

Information on the transfer of patients with cyclosporine therapy to Prograf® is given at the end of the section on "Correction of the dose of the drug in special patient populations."

Recommended doses for treatment of rejection after allografts of other organs.

Recommendations for drug dosing PROGRAP® for patients after lung, pancreas and small intestine allotransplantation are based on data from selected prospective clinical trials.After lung transplantation, Prograf® is used in the initial dose of 0.10-0.15 mg / kg / day, pancreas allotransplantation - at an initial dose of 0.2 mg / kg / day. In patients after allografting of the small intestine, the initial dose of the drug is 0.3 mg / kg / day.

Correction of the dose of the drug in special populations of patients.

Patients with hepatic insufficiency

Patients with severe hepatic impairment may require a dose reduction in order to maintain the target minimum level of the drug within the recommended values.

Patients with renal insufficiency

Since the pharmacokinetics of tacrolimus does not vary with renal function, no dose adjustment is required. However, due to the presence of nephrotoxic action in tacrolimus, it is recommended to closely monitor renal function (including serum creatinine concentration, creatinine clearance and diuresis level).

Children

To achieve similar concentrations of the drug in the blood, children usually require doses that are 1.5 to 2 times higher than doses for adults.

Elderly patients

Currently, there is no evidence of the need to adjust the dose of the drug for elderly patients.

Transfer from cyclosporine to Prograf®

Simultaneous use of cyclosporine and Prograf® can increase the half-life of cyclosporine and increase toxic effects. Therefore, care must be taken when transferring patients from cyclosporine to Program® therapy. Treatment with Prograf® should be started after an assessment of the concentrations of cyclosporin in the 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, the drug is prescribed 12-24 hours after the withdrawal of cyclosporine. After the transfer of the patient, it is necessary to continue monitoring the concentrations of cyclosporine in the patient's blood in connection with the possibility of impaired clearance of cyclosporine.

Recommendations for monitoring the therapeutic concentration of tacrolimus in the blood

The choice of the dose of the drug should be based on the clinical assessment of rejection and tolerability of the drug in each individual patient. In order to optimize the dosage of the drug, tacrolimus concentration in whole blood is used to determine the concentration of tacrolimus using immune methods, including a semi-automated enzyme-linked immunosorbent assay (MICA).Comparison of data on the concentration of tacrolimus in the blood published in the literature with individual clinical indicators should be conducted with caution and based on knowledge and understanding of the valuation method used.

In the postoperative period, it is important to monitor the minimum concentrations of tacrolimus in whole blood. When oral administration of the drug to determine the minimum concentrations of tacrolimus in the blood, it is necessary to obtain blood samples 12 hours after taking the drug, immediately before the next dose. The frequency of tacrolimus concentration in the blood should depend on clinical needs. Since Prograf® is a drug with low clearance, after adjustment of the dose, the time to reach the equilibrium minimum concentration of tacrolimus in the blood can be several days. 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. The minimum concentrations of tacrolimus in the blood also need to be monitored after changing the dose of Program®, the immunosuppression regimen, or after sharing with the drugs,affecting the concentration of tacrolimus in whole blood.

The results of clinical studies indicate that treatment with Prograf® is the most successful when the minimum tacrolimus concentration in the blood does not exceed 20 ng / ml. When interpreting data on the concentration of the drug in whole blood, it is important to assess the clinical state of the patient.

In clinical practice, in the early post-transplant period, the minimum concentrations of the drug in whole blood usually range from 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, the concentration of the drug in the blood varies 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 phenomena of immunosuppressants is difficult to establish accurately.

Many of the adverse events presented below are reversible and / or decreased with a reduced dose.Within each frequency group, undesirable phenomena are presented in descending order of gravity. Undesirable phenomena classified by organs and systems are listed below in order of decreasing frequency of detection: very often (> 1/10), often (> 1/100 to <1/10), infrequently (> 1/1000 to <1 / 100), rarely (from> 1/10 000 to <1/1 000), very rarely (<1/10 000), the frequency is unknown (to establish the frequency of which the data is insufficient).

Cardiovascular Heart System

often: ischemic coronary disorders, tachycardia

infrequently: ventricular arrhythmias and cardiac arrest, heart failure, cardiomyopathies, ventricular hypertrophy, supraventricular arrhythmias, heart palpitations, abnormal ECG parameters, irregular heartbeat and heart rate rhythm and heart rate rarely: pericardial effusion

very rarely: abnormal echocardiogram

Vascular system

Often: arterial hypertension

often: bleeding, thromboembolic and ischemic complications, violation of peripheral circulation, arterial hypotension infrequently: infarction, deep vein thrombosis, shock

System of blood and lymphatic system

often: anemia, leukopenia, thrombocytopenia, leukocytosis, a decrease or increase in hemoglobin and / or hematocrit.

infrequently: Coagulopathy, abnormalities in coagulogram, pancytopenia, neutropenia

rarely: thrombotic thrombocytopenic purpura, hypoprothrombinemia

Nervous system

very often: tremor, headache

often: convulsive syndrome of various genesis, 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

very rarely: myasthenia gravis

Зrhenium

often: blurred vision, photophobia, eye diseases

infrequently: cataract

rarely: blindness

Organs of hearing and balance

often: ringing in the ears

infrequently: hearing loss

rare: sensorineal deafness

very rare: hearing impairment

Respiratory system and mediastinum

often: shortness of breath, pulmonary parenchymal disorders, pleural effusion, pharyngitis, cough, nasal congestion, rhinitis

infrequently: respiratory insufficiency, respiratory tract disorders, asthma

rare: acute respiratory distress syndrome

Gastrointestinal tract very often: diarrhea, nausea

often: inflammatory diseases of the gastrointestinal tract, gastrointestinal ulcers and perforations, gastrointestinal bleeding, stomatitis and ulceration of the oral mucosa, ascites, vomiting, gastrointestinal and abdominal pain, indigestion, constipation, flatulence, feelings of bloating and swelling in the abdomen , a loose stool, symptoms of violations of the gastrointestinal tract infrequent: paralytic intestinal obstruction (paralytic ileus), peritonitis, acute and chronic pancreatitis, increased activity of amylase in the blood, gastroesophageal reflux disease, impaired gastric evacuation function

rare: subileus, pancreatic pseudocysts

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 rare: nephropathy, hemorrhagic cystitis Skin and subcutaneous tissue

often: itching, rash, alopecia, acne, hyperhidrosis

infrequently: dermatitis, photosensitivity

rare: toxic epidermal necrolysis (Lyell's syndrome)

Very rare: Stevens-Johnson syndrome Musculoskeletal system and connective tissue

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

infrequently: articular disorders

Endocrine system

rare: hirsutism

Metabolism and nutrition disorders

very often: hyperglycemia, diabetes, hyperkalemia

often: hypomagnesemia, hypophosphatemia, hypokalemia, hypocalcemia, hyponatremia, hypervolemia, hyperuricemia, decreased appetite, anorexia, metabolic acidosis, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, electrolyte infrequent infrequently: dehydration, hypoproteinemia, hyperphosphatemia, hypoglycemia

The immune system

Allergic reactions

In patients who took tacrolimus, allergic and anaphylactic reactions were observed.

Infections and invasions

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- virus, were observed against the background of immunosuppressive therapy, including treatment with Prograf®.

Injuries, poisonings, complications of procedures

often: primary transplant dysfunction

Benign, malignant and unidentified neoplasms 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 complications

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, worsening of well-being, increased lactate dehydrogenase activity in the blood, a decrease in body weight rare: thirst, loss of balance, a feeling of stiffness in the chest, ulcer (at the injection site), movement difficulties are very rare: an increase in fat mass

Liver and bile ducts

often: increased liver enzymes, liver dysfunction, cholestasis and jaundice, liver cell damage and hepatitis, cholangitis rare: thrombosis of the hepatic artery, obliterating endophlebitis of the hepatic veins

very rare: hepatic insufficiency, stenosis of the bile ducts

Reproductive system and mammary glands infrequently: dysmenorrhea and uterine bleeding

Mental disorders

very often: insomnia

often: anxiety, confusion and disorientation, depression, depressed mood,emotional disorders, nightmares, hallucinations, mental disorders infrequently: psychotic disorders.

Overdose:

Information on overdose is limited. Several episodes of accidental overdoses were reported. Symptoms included tremor, headache, nausea, vomiting, infection, urticaria, lethargic state, increased urea nitrogen in the blood, serum creatinine and alanine aminotransferase.

Currently there are no antidotes to tacrolimus. In case of an overdose, standard measures and symptomatic treatment should be taken. Given the high molecular weight of tacrolimus, poor solubility in water, and pronounced binding to erythrocytes and plasma proteins, dialysis is ineffective. In individual patients with very high concentrations of tacrolimus in the blood, hemofiltration or diafiltration was effective.

Interaction:

Metabolic interactions

Tacrolimus, located in the systemic blood stream, is metabolized in hepatic cytochrome CYP3A4. There is also information about the course of metabolism of tacrolimus in the gastrointestinal tract in the cytochrome system CYP3A4, located in the wall of the intestine. Simultaneous administration of drugs or medicinal plants with established inhibitory or inducing action on CYP3A4 may accordingly increase or decrease the concentration of tacrolimus in the blood. Therefore, to maintain adequate and permanent exposure of tacrolimus, it is recommended to monitor the concentration of tacrolimus in the blood and, if necessary, adjust the dose of Prograph.

Inhibitors of Metabolism

Based on clinical experience, it was found that the concentration of tacrolimus in the blood can significantly increase the following medicines: antifungal agents (ketoconazole, fluconazole, itraconazole, voriconazole), macrolide antibiotics (erythromycin), HIV protease inhibitors (ritonavir). When these drugs are prescribed, tacrolimus doses are often required. Less pronounced drug interaction was observed with the simultaneous use of drugs tacrolimus with clotrimazole, clarithromycin, josamycin, nifedipine, nicardipine, diltiazem, verapamil, danazol, ethinyl estradiol, omeprazole and nefazodone.

In studies in vitro it was shown that the following substances are potential inhibitors of tacrolimus metabolism: bromocriptine, cortisone, dapsone, ergotamine, gestodene, lidocaine, mephenytoin, miconazole, midazolam, nilvadipine, norethisterone, quinidine, tamoxifen, (triacetyl) oleandomycin.

It is also recommended to avoid grapefruit juice in connection with the possibility of an increase in the level of tacrolimus in the blood. Lansoprazole and ciclosporin can potentially inhibit SURCA4-mediated metabolism of tacrolimus and increase its concentration in the blood. Inductors of metabolism

Based on clinical experience, it was found that the concentration of tacrolimus in the blood can significantly reduce the following medicines: rifampicin, phenytoin, St. John's wort (Hypericum perforatum). With the simultaneous administration of these drugs with tacrolimus, an increase in tacrolimus doses may be required. Clinically significant interactions were observed with phenobarbital.

Corticosteroids in maintenance doses usually reduce the concentration of tacrolimus in the blood. High doses of prednisolone or methylprednisolone, used to treat acute rejection, may increase or decrease the level of tacrolimus in the blood. Carbamazepine, metamizole and isoniazid can reduce the concentration of tacrolimus in the blood.

Effect of tacrolimus on the metabolism of other drugs

Tacrolimus inhibits CYP3A4 and with simultaneous admission may affect the drugs metabolized in the system CYP3A4. The half-life of cyclosporin with simultaneous application with tacrolimus increases. Synergistic / additive nephrotoxic effects may also occur. For these reasons, simultaneous administration of cyclosporine and tacrolimus is not recommended, and in the appointment of tacrolimus to patients who have previously taken ciclosporin, care must be taken. Tacrolimus increases the level of phenytoin in the blood.

As tacrolimus can reduce the clearance of hormonal contraceptives, it is important to be careful when choosing contraceptives.

Data on the interaction of tacrolimus with statins are limited. Clinical observations allow us to conclude that the simultaneous admission with tacrolimus pharmacokinetics of statins does not change.

Experimental studies in animals have shown that tacrolimus Potentially able to reduce clearance and increase half-lifepentobarbital and phenazone

Other potential interactions that increase the systemic exposure of tacrolimus

Prokinetic means (metoclopramide, cisapride). Cimetidine. Magnesium hydroxide and aluminum hydroxide.

Other Potential Adverse Drug Interactions

The simultaneous use of tacrolimus with drugs that have nephro- or neurotoxicity (eg, aminoglycosides, gyrase inhibitors, vancomycin, cotrimoxazole, non-steroidal anti-inflammatory drugs, ganciclovir, acyclovir) can enhance these effects.

As a result of the combined use of tacrolimus with amphotericin B and ibuprofen, nephrotoxicity increased.

As tacrolimus may promote or exacerbate hyperkalemia, high potassium doses or potassium-sparing diuretics should be avoided (amiloride, triamterene, spironolactone).

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

Binding to proteins

Tacrolimus actively binds to blood plasma proteins. Take into account the possible competitive interaction of tacrolimus with drugs that have a high affinity for plasma proteins (non-steroidal anti-inflammatory drugs, oral anticoagulants, oral antidiabetics).

Incompatibility

Tacrolimus is incompatible with polyvinyl chloride (PVC). Tubes, syringes and other equipment 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 plasma glycemia, electrolyte concentration (especially potassium), hepatic and renal function, hematological parameters, coagulogram, proteinemia level. In the presence of clinically significant changes, correction of immunosuppressive therapy is necessary.

When using drugs tacrolimus should avoid the appointment of herbal preparations containing St. John's wort (Hypericum perforatum), 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 vary 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 cardiac hypertrophy, reported as cardiomyopathy, were rare, but were observed in patients taking tacrolimus preparations. In most cases, myocardial hypertrophy was reversible and was observed at concentrations (Co) 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 an intensive immunosuppressive therapy, especially for children, before and after transplantation (after 3 and 9-12 months) it is necessary to carry out echocardiographic and ECG monitoring.If anomalies are detected, consideration should be given to reducing the dose of tacrolimus or substituting tacrolimus for another immunosuppressant.

Tacrolimus may cause lengthening of the interval QT, with violations of the rhythm of the heart such as "pirouette" (bidirectional spindle-shaped ventricular tachycardia) was not observed. In the treatment of patients with diagnosed congenital syndrome of an elongated interval QT or suspicion of such a condition should be very careful.

Patients treated with tacrolimus may develop post-transplant lymphoproliferative diseases (PTLZ) associated with the Epstein-Barr virus. With the simultaneous use of the drug with antilymphocytic antibodies, the risk of PTLZ increases. In recipients younger than 2 years with a negative test result for the capsid antigen of the Epstein-Barr virus, there is an increased risk of PTLZ. Therefore, in this group of patients, careful monitoring of the Epstein-Barr virus, for example, using a polymerase chain reaction (PCR), is recommended before and during treatment. 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, symptoms appear that are characteristic of the syndrome of reversible posterior encephalopathy: headache, mental disorders, convulsions and visual disturbances, it is necessary to perform magnetic resonance imaging. When confirming the diagnosis, it is necessary to exercise adequate control over arterial pressure and convulsions, and immediately stop the systemic administration of tacrolimus. If these measures are taken, this condition is completely reversible in most patients.

In patients receiving immunosuppressive therapy, including tacrolimus, increased risk of opportunistic infections (caused by bacteria, fungi, viruses, protozoa). Among these infections, nephropathy associated with BV-virus is noted, as well as associated with JC-virus progressive multifocal leukoencephalopathy (PML). Such infections are often associated with a 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,having signs of impaired renal function or neurologic symptoms on the background of immunosuppressive therapy.

Immunosuppressive therapy increases the risk of malignant neoplasms. It is recommended to limit insolation and ultraviolet irradiation, wear appropriate clothing, use sunscreens with a high protective factor in order to reduce the risk of developing malignant skin tumors.

The risk of developing a secondary cancer is unknown.

Accidental administration of the solution Program in the artery or perivascular space can cause irritation in the area of administration.

Form release / dosage:

Concentrate for the preparation of a solution for intravenous administration of 5 mg / ml.

1 ml per ampoule with a capacity of 2 ml of colorless transparent glass with a ring and a dot. 10 ampoules per plastic cell pack. One package together with instructions for use in a cardboard box.

Packaging:ampoules (10) - packings, cellular contour-packs, cardboard

Storage conditions:

Protected from light at a temperature of no higher than 25 ° C.

After dilution, the solution is stored in a glass, polyethylene or polypropylene vessel at a temperature of 2 to 8 ° C for 24 hours.

Keep out of the reach of children.

Shelf life:

2 years

The drug should not be used after the expiration date indicated.

Terms of leave from pharmacies:On prescription

Registration number:LS-000922

Date of registration:24.02.2011

The owner of the registration certificate:Astellas Farma Europe BVAstellas Farma Europe BV Netherlands

Manufacturer: & nbsp

ASTELLAS Ireland, Co.Ltd. Ireland

Representation: & nbspASTELLAS PHARMA YUROP BV ASTELLAS PHARMA YUROP BV Netherlands

Information update date: & nbsp02.09.2015

Illustrated instructions

Instructions

Prograph® (Prograf®)