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

Name of components	Capsules 0.5 mg	Capsules 1 mg	Capsules 5 mg
Active substance:
Tacrolimus	0.5 mg	1.0 mg	5.0 mg
Excipients:
Hepromellosis	0.5 mg	1.0 mg	5.0 mg
Croscarmellose sodium	0.5 mg	1.0 mg	5.0 mg
Lactose Monohydrate	62.85 mg	61.35 mg	123,60 mg
Magnesium stearate	0.65 mg	0.65 mg	1.4 mg
Capsule shell composition:
Titan diocid (E 171)	0.338 mg	0.395 mg	0.564 mg
The iron oxide is yellow (E 172)	0.048 mg	-	-
The iron oxide is red (E 172)	-	-	0.008 mg
Purified water	4.2 mg	4.2 mg	6.0 mg
Gelatin	23.414 mg	23.405 mg	33.428 mg

Composition of ink inscriptions on capsules (Opacode S-1-15083 - on capsules 0.5 mg, 1 mg)

(Opacode S-1-7305HV - 5 mg capsules)

Name	amount
Auxiliary substances	Capsules 0,5 mg, 1 mg	Capsules 5 mg
Pharmaceutical glaze (shellac solution in ethanol)	60,700 %	25,578 %
Lecithin (Soybean)	0,480 %	0,160%
Simethicone	0,010%	_
Dimethylpolysiloxane	-	0,001 %
Titanium dioxide E 171	_	38,500 %
Iron colorant red oxide E172	20,000 %	.
Giprollos	0,300 %	-
Purified water **	4,000 %	3,000%
Brand alcohol SDA FOR ** (Ethanol, Methanol)	5,000 %
Denatured alcohol **	-	31,761%
n-butyl alcohol **	9,510%
Total relative amount of ingredients in ink, in percent	100,000%	100,000 %

** - There are no solvents in the finished dosage form.

Description:

Capsules 0.5 mg: hard gelatin capsule size no. 5, body and lid are opaque, light yellow, with an overprint of red color "0.5 mg" on the cap of the capsule and "[f]607" on the shell of the capsule. The contents of the capsules are white powder.

Capsules 1 mg: hard gelatin capsule size no. 5, body and cap opaque, white, with an overprint of red color "1 mg" on the cap of the capsule and "[f]617" on the shell of the capsule. The contents of the capsules are white powder.

Capsules 5 mg: hard gelatin capsules with a size of 4, the case and the lid are opaque, grayish red, with a white overprint "5 mg" on the cap of the capsule and "[f]657" on the shell of the capsule. The contents of the capsules are white powder.

Pharmacotherapeutic group:immunosuppressive agent - calcineurin inhibitor

Pharmacodynamics:

At the molecular level, effects and intracellular cumulation of tacrolimus are due to binding to the cytosolic protein (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, γ-interferon), T cell activation, interleukin-2 receptor expression, and T-helper dependent proliferation of B cells.

Pharmacokinetics:

Absorption

It is established that in the human body tacrolimus quickly absorbed in the gastrointestinal tract. When administered orally with ProGraph®, the mean time to reach C_maxis 1-3 hours. In some patients tacrolimus Absorbed over a long period of time, providing a relatively gentle absorption profile. Bioavailability of tacrolimus when administered to capsules Prograf® is on average 20-25%. In most patients, after liver transplantation on the background of oral administration (0.30 mg / kg / day), equilibrium concentrations of tacrolimus were reached within 3 days.

In studies involving healthy volunteers, the bioequivalence of Prograf® capsules was 0.5 mg, 1.0 mg, and 5.0 mg when taken in equal doses.

The highest rate and degree of absorption of tacrolimus is achieved by taking Prograf® capsules on an empty stomach. The speed and extent of absorption of tacrolimus while taking with food are reduced, especially in the case of high levels of fat in the diet.

The influence of foods rich in carbohydrates on the absorption of tacrolimus is less pronounced. In stable patients after liver transplantation, bioavailability decreased with simultaneous administration of Prograf® capsules with moderate-fat food (34% of calories). There was also a decrease in the area under the pharmacokinetic curve AUC (27%), the maximum concentration of C_max (50%) and an increase t_max (173%) in whole blood.

In a study involving stable patients after kidney transplantation, when taking Prograf® capsules immediately after a standard breakfast, the effect of food on the bioavailability of tacrolimus was less pronounced. There was a decrease AUC (by 2-12%) and C_max(by 15-38%), and an increase t_max(Ha 38-80%).

Isolation of bile does not affect the absorption of tacrolimus.

On the background of therapy with Prograf® capsules, when the equilibrium state is reached, a high correlation between AUC and minimum concentrations of tacrolimus in whole blood. Therefore, monitoring the minimum concentrations of tacrolimus in whole blood can serve as a method that provides an adequate assessment of the systemic exposure of tacrolimus.

Distribution 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 with allowance for plasma concentrations is about 1300 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 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.

Carefully:

Pregnancy and lactation:

Pregnancy

The results of studies involving people show that the drug can penetrate the placenta. Some data on the application of tacrolimus in transplanted patients indicate that there is no higher risk of adverse effects of the drug on the course and outcome of pregnancy on compared with other immunosuppressants. There are reports of spontaneous abortions. There are no other epidemiological data on this issue. Since the safety of tacrolimus in pregnant women is not sufficiently established, the drug is taken during pregnancy only in the absence of a safer alternative and only in those cases where the benefits of treatment justify the potential risk to the fetus.In order to identify potential unwanted reactions tacrolimus is recommended to monitor the condition of newborns whose mothers during pregnancy were taking tacrolimus (in particular, pay attention to the kidney function). In rats and rabbits tacrolimus had embryotoxic and fetotoxic effects in doses that were toxic to the mother's body. When using toxic doses

tacrolimus in female rats, there was a violation of the reproductive function, including childbirth, and the offspring lost weight at birth, decreased viability and stunted growth.

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 taking Prograf® should refrain from breastfeeding.

Fertility

Pre-clinical studies in rats showed a negative effect of tacrolimus on male fertility, which was reflected in a decrease in the number and mobility of spermatozoa.

Dosing and Administration:

Therapy with Prograf® requires careful monitoring by qualified personnel and the necessary equipment. Prescription® or the modification of immunosuppressive therapy can only be performed by physicians with experience of immunosuppressive therapy in patients with transplanted organs.

The uncontrolled transfer of patients from one drug tacrolimus to another (including the transition from conventional capsules to prolonged capsules) is unsafe. This can lead to rejection of the transplant or an increase in the incidence of side effects, including hypo- or hyperimmunosuppression due to the appearance of clinically significant differences in the exposure of tacrolimus. The patient should take one of the dosage forms of tacrolimus in accordance with the recommended dosage regimen. The change in dosage form or dosage regimen should be carried out only under the supervision of a specialist in the field of transplantology. After the transfer, it is necessary to carefully monitor the concentration of tacrolimus in the blood and adjust the dose of the drug to maintain the systemic exposure of tacrolimus at an adequate level.

When you skip Prograf® capsules should be taken on time in the next dose. A double dose of the drug should not be taken.

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 evaluation of the risk of rejection and individual drug tolerance, as well as on the monitoring of tacrolimus concentration in the blood (see section "Recommendations for monitoring 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, Program® in the capsule dosage form is administered orally; If necessary, the contents of the capsules can be mixed with water and injected through a nasogastric tube.

Dosing and Administration

The daily dose of Program® in capsule form is divided into 2 doses (in the morning and in the evening) in equal doses. Capsules should be taken immediately after they are removed from the blister. Desiccant (package with silica gel), embedded in the packaging, is not edible.

Capsules are washed down with a liquid, preferably water. To achieve maximum absorption, capsules should be taken on an empty stomach, 1 hour or 2-3 hours after eating.

Duration of the drug

To prevent rejection of the graft, the state of immunosuppression must be maintained at all times, hence the duration of therapy is not limited.

Liver transplantation Primary immunosuppression - adults

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

If the patient's condition does not allow taking the medicine inside, it is necessary to start intravenous therapy at a dose of 0.01-0.05 mg / kg / day, administering Prograf® as a continuous 24-hour infusion.

Primary immunosuppression is children

The initial dose of 0.30 mg / kg / day of Program ® 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 drugs inside, intravenous therapy with Prograf® should be started with a dose of 0.05 mg / kg / day as a continuous 24-hour infusion.

Supportive therapy - adults and children

In the posttransplant period, the dose of Prograf® is usually reduced. In some cases, it is possible to cancel preparations of concomitant immunosuppressive therapy, leaving Prograf® as monotherapy. Improvement of the patient's condition after transplantation can change the pharmacokinetics of tacrolimus, and there will be a need for dose adjustment.

Treatment of rejection - adults and children

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

When transferring patients to Prograf® capsule therapy, 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 "Correction of the dose of the drug in special patient populations."

Kidney Transplantation

Primary immunosuppression - adults

Oral therapy with Prograf® capsules should be started at a dose of 0.20-0.30 mg / kg / day, divided into two doses (for example, in the morning and in the evening). The drug should be started within 24 hours after the operation is completed. If the patient's condition does not allow 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.

Primary immunosuppression is children

The initial dose of 0.30 mg / kg / day of Prograf® capsules should be divided into two doses (for example, in the morning and in the evening). If the patient's clinical condition does not allow him to take the drug inside, intravenous therapy should be started at a dose of 0.075-0.100 mg / kg / day as an intravenous infusion within 24 hours.

Supportive therapy - adults and children

In the course of maintenance therapy, the doses of Prograf® are usually reduced. In some cases, it becomes possible to cancel the concomitant immunosuppressants, leaving Prograf® as the basic component of the dual therapy.Improvement of the patient's condition after transplantation can change the pharmacokinetics of tacrolimus, and a need for dose adjustment will arise.

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® capsule therapy, 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 Prograf®) or without prescribing antibodies in clinically stable patients. Following the induction of antibodies, oral therapy with Prograf® capsules should be started at a dose of 0.075 mg / kg / day,divided into two doses (for example, in the morning and in the evening), 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 should be 0.30 mg / kg / day and be administered 8-12 hours after discontinuation of the intravenous infusion.

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

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 a need for dose adjustment will arise.

Treatment of rejection reaction - adults and children

To treat episodes of rejection, higher doses of Prograph® capsules should be used in combination with additional corticosteroid therapy and short courses of mono- / polyclonal antibody administration.

When transferring patients to Program® capsules, the initial daily dose (for adults - 0.15 mg / kg / day, for children - 0.2-0.3 mg / kg / day) should be divided into two doses (for example, in the morning and in the evening).

Information on the transfer of patients with cyclosporine therapy 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 dosing Prograf® 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 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 change with renal function, no dose adjustment is required. However, due to the presence of nephrotoxic action in tacrolimus, it is recommended to carefully 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 1.5-2 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 drugs of cyclosporine and tacrolimus may increase the half-life of cyclosporine and enhance toxic effects. Therefore, care must be taken when transferring patients from cyclosporine to tacrolimus therapy. Treatment with capsules Prograf® should be started after an assessment of the concentrations of cyclosporine in the blood and the clinical state of the patient. Transition to Prograf® should be postponed in the presence of elevated concentrations of cyclosporine in the patient's blood. In practice, Prograf® is administered 12-24 hours after cyclosporine withdrawal. 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 dose of Prograf® capsules should be based on the clinical assessment of rejection and tolerability of the drug in each individual patient. To optimize dosing, tacrolimus concentration in whole blood is measured using immune methods, including semi-automatic enzyme-linked immunosorbent assay (MIFA). Comparison of data on the concentration of tacrolimus in the blood published in the literature with individual clinical indicators should be conducted with caution and based on knowledge and understanding of the valuation method used.

In the postoperative period, it is important to monitor the minimum concentrations of tacrolimus in whole blood. When oral administration of Prograf® capsules to determine the minimum concentrations of tacrolimus in the blood, blood samples must be obtained 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.Minimal tacrolimus concentrations 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 should also be monitored after changing the dose of Prograf® capsules, the immunosuppression regimen, or after joint application with drugs that affect the concentration of tacrolimus in whole blood.

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

In clinical practice, in the early posttransplant period, the minimum concentrations of tacrolimus 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, tacrolimus concentrations in the blood range from 5 to 15 ng / ml.

Side effects:In connection with the characteristics of the underlying disease and a large number of drugs used

Simultaneously after transplantation, the profile of undesirable reactions of immunosuppressants is difficult to establish accurately.

Many of the undesirable reactions presented below are reversible and / or reduced with a lower dose. Oral reception is associated with a lower risk of adverse reactions compared with intravenous administration of the drug. Within each frequency group, undesirable phenomena are presented in descending order of gravity. Undesirable reactions classified by organs and systems are listed below in order of decreasing detection frequency: very often (> 1/10), often (from > 1/100 up to < 1/10), infrequently > 1/1000 before < 1/100), rarely (from >_1/10 000 before <1/1 000), rarely (< 1/10 000), frequency is unknown (to establish the frequency of which is giveninsufficient).

Heart failure often: ischemic coronary

disorders, tachycardia; infrequently: ventricular arrhythmias and cardiac arrest, heart failure, cardiomyopathies, ventricular hypertrophy, supraventricular arrhythmias, palpitations, abnormal ECG,violations of the rhythm and heart rate and heart rate; rarely: pericardial effusion; very rarely: pathological changes on the echocardiogram, lengthening of the interval QT on an electrocardiogram, a disturbance of the rhythm of the heart such as "pirouette" (bidirectional spindle-shaped ventricular tachycardia). Vascular disorders are very common: hypertension;

often: bleeding, thromboembolic and ischemic complications, peripheral circulatory disorders, vascular hypotension; infrequently: a heart attack, deep vein thrombosis of the extremities, shock.

Violations from the blood and lymphatic system

often: anemia, leukopenia, thrombocytopenia, leukocytosis, a decrease or increase in hemoglobin and / or hematocrit, deviations in the analysis of erythrocytes; infrequently: coagulopathy, abnormalities in coagulogram, pancytopenia, neutropenia; rarely: thrombotic thrombocytopaic purpura, hypoprothrombinemia; frequency unknown: partial red cell aplasia, agranulocytosis, hemolytic anemia.

Violations from the nervous systems

very often: tremor, headache; often: convulsions, impaired consciousness,paresthesia and dysesthesia, peripheral neuropathies, dizziness, violation of writing, nervous system disorders; infrequently: coma, hemorrhages in the central nervous system and disorders of cerebral circulation, paralysis and paresis, encephalopathy, speech and articulation disorders, amnesia; rarely: increased muscle tone; very rarely: myasthenia gravis.

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

Hearing disorders and labyrinthine disturbances often: noise (ringing) in the ears; infrequently: hearing loss; rarely: neurosep- sory deafness; very rarely: hearing impairment.

Disturbances from respiratory system, chest organs and the mediastinum

often: dyspnea, pulmonary parenchymal disorders, pleural effusion, pharyngitis, cough, nasal congestion, rhinitis; infrequent: respiratory failure, respiratory tract disorders, asthma; rarely: acute respiratory distress syndrome.

Disorders from the gastrointestinal tract

very often: diarrhea, nausea; often: inflammatory diseases of the gastrointestinal tract, gastrointestinal ulcers and perforations, gastrointestinal bleeding, stomatitis and ulceration of the oral mucosa, ascites, vomiting, gastrointestinal and abdominal pain, dyspepsia, constipation, flatulence, feelings of swelling and abdominal distension, loose stools, symptoms of gastrointestinal disturbances; infrequently: paralytic intestinal obstruction (paralytic ileus), peritonitis, acute and chronic pancreatitis, increased level of amylase in the blood, gastroesophageal reflux disease, impaired gastric evacuation function; rarely: subileus, pancreatic pseudocysts.

Disorders from 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; highly rarely: nephropathy, hemorrhagic cystitis.

Disturbances from the skin and subcutaneous tissues

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

infrequently: dermatitis, photosensitivity;

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

rarely: Stevens-Johnson syndrome.

Disturbances from musculoskeletal and connective tissue often: arthralgia, muscle cramps, pain in the limbs, back pain; infrequently: articular disorders.

Disorders from the endocrine system

rarely: hirsutism.

Disorders from the metabolism and nutrition

Often: Hyperglycemia, diabetes mellitus, hyperkalemia; often: hypomagnesemia, hypophosphatemia, hypokalemia, hypocalcemia, hyponatremia, hypervolemia, hyperuricemia, decreased appetite, anorexia, metabolic acidosis, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, electrolyte disturbances; infrequently: dehydration, hypoproteinemia, hyperphosphataemia, hypoglycemia.

Immune system disorders

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

Infectious and parasitic diseases

Against the background of tacrolimus therapy, as well as other immunosuppressants, the risk of local and generalized infectious diseases increases (viral, bacterial, fungal, prozoic). 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 JCvirus, were observed on background of immunosuppressive therapy, including therapy with Prograf®.

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

In practice, there were errors in the use of tacrolimus preparations, including unreasonable or uncontrolled transfer of patients from one dosage form tacrolimus (standard or prolonged) to another, and also recorded cases of graft rejection (according to available data, the frequency can not be estimated).

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

Patients receiving immunosuppressive therapy have a higher risk of malignant tumors. With the application of tacrolimus, the appearance of both benign and malignant neoplasms, including the Epstein-Barr virus-associated lymphoproliferative diseases and skin cancer.Common disorders and disorders at the injection site are often: asthenia, febrile conditions, swelling, pain and discomfort, increased alkaline phosphatase activity in the blood, increased body weight, impaired body temperature perception;

infrequently: multiple organ failure, influenza-like syndrome, impaired perception of the temperature of the environment, a feeling of squeezing in the chest, a sense of anxiety, worsening of well-being, increased lactate dehydrogenase activity in the blood, weight loss; rarely: thirst, loss of balance (falling), a feeling of stiffness in the chest, obstruction of movement, ulcer; very rarely: an increase in the mass of adipose tissue.

Disorders from the liver and bile ducts

often: increased levels of hepatic enzymes, impaired liver function, pathological changes in functional liver tests, cholestasis and jaundice, liver cell damage and hepatitis, cholangitis;

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

Violations of the genitals and mammary gland infrequently: dysmenorrhea and uterine bleeding.

Disorders of the psyche very often: insomnia; often: anxiety, confusion consciousnesses and disorientation, depression, depressed mood, affective disorders, nightmares, hallucinations, mental disorders; infrequently: psychotic disorders.

Overdose:

Information on overdose is limited. Several episodes of occasional overdoses have been reported in patients taking tacrolimus medications. 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.In cases of oral overdosage, gastric lavage and / or the use of adsorbents (eg, activated charcoal) may be effective if these measures are taken shortly after taking the drug.

Interaction:

Metabolic interactions Tacrolimus, located in the systemic blood flow, metabolized hepatic cytochrome CYP3A4. When taken orally tacrolimus is also metabolized in the intestinal system cytochrome CYP3A4.

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. To maintain adequate and permanent exposure of tacrolimus while simultaneous administration with drugs that can change activity CYP3A4 or have a different effect on the pharmacokinetics of tacrolimus, it is recommended to monitor the concentration of tacrolimus in the blood and, if necessary, adjust the dose or cancel the drug. You should also monitor the interval QT (by electrocardiography), renal function and possible side effects.

Inhibitors of Metabolism

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, nelfinavir, saquinavir) or hepatitis C virus protease inhibitors (eg, telaprevir, boceprevir). When prescribing these drugs with tacrolimus, tacrolimus doses may need to be reduced in almost all patients. Less pronounced drug interaction was observed with the simultaneous use of drugs tacrolimus with clotrimazole, clarithromycin, josamycin, nifedipine, nicardipine, diltiazem, verapamil, amiodarone, danazol, ethinyl estradiol, omeprazole and nefazodone.

In studies in vitro it was shown that the following substances are potential inhibitors of tacrolimus metabolism: bromocriptine, cortisone, dapsone, ergotamine, gestodene, lidocaine, mephenytoin, miconazole, midazolam, nilvadipine, norethisterone, quinidine, tamoxifen, (triacetyl) olsandomycin.It is recommended to avoid grapefruit juice in connection with the possibility of increasing the level of tacrolimus in the blood. Lansoprazole and ciclosporin can potentially inhibit CYP3A4- tacrolimus metabolism and increase its concentration in the blood.

Inductors of Metabolism Based on clinical experience, it has been found that the concentration of tacrolimus in the blood can significantly reduce the following drugs: rifampicin, phenytoin, St. John's wort (Hypericum perforatum). With the simultaneous administration of these drugs with tacrolimus, you may need to increase the dose of Prograf "in almost all patients.

Clinically significant interactions were observed with phenobarbital.

Corticosteroids in maintenance doses, the concentration of tacrolimus in the blood is usually reduced. 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. Also can be observed siergic / additive nephrotoxic effects. For these reasons, simultaneous administration of cyclosporine and tacrolimus is not recommended, and when administered tacrolimus to patients who had 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 the half-life of pentobarbital and phenazone.

Other potential interactions that increase systemic exposure of tacrolimus

Prokinetic means (metoclopramide, cisapride). Cimetidine. Hydroxide of magnesium and aluminum.

Other potentially unfavorableThe simultaneous use of tacrolimus with drugs that have nephro- or neurotoxicity (for example, aminoglycosides, inhibitors of gyrase, vancomycin, cotrimoxazole, non-steroidal anti-inflammatory drugs, hapciclovir, 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. It should be taken into account the possible competitive interaction of tacrolimus with drugs,which have a high affinity for blood plasma proteins (iseroidal inflammatory drugs, oral anticoagulants, oral antidiabetics).

Incompatibility

Tacrolimus is incompatible with polyvinyl chloride (PVC). Tubes, syringes and other equipment used in the preparation of a suspension of Program® capsules should not contain PVC.

Special instructions:

In the initial post-transplant period, the following parameters should be regularly monitored: blood pressure, ECG, neurological status and vision, fasting blood glucose, electrolyte concentration (especially potassium), hepatic and renal function, hematological parameters, coagulogram, proteinemia level. In the presence of clinically significant changes, correction of immunosuppressive therapy is necessary.

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 Mr.ifateflaxm phenomena, including rejection graft or other side effects that could be due to hypo- or hyperimmunosuppression caused by clinically significant differences at exposure tacrolimus. The patient should be kept on one of the dosage forms tacrolimus from relevant regime dosing; change dosage form or dosing regimen should be carried out only under the supervision of a specialist in the field of transplantology.

At simultaneous appointment with tacrolimus of other preparations, especially strong inhibitors CYP3A4 (eg, telaprevir, boceprevir, ritonavir, ketoconazole, voriconazole, itraconazole, telithromycin or clarithromycin) or isoenzyme inducers CYP3A4 (eg, rifampicin, rifabutin) - concentration in the blood of tacrolimus must monitored for timely dose adjustment.

When using drugs tacrolimus should avoid the appointment of herbal products 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 therapeutic effect of the drug.With diarrhea, tacrolimus concentrations 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 rarely, but were observed in patients, who took tacrolimus. In most cases myocardial hypertrophy was reversible and was observed at concentrations (Co) tacrolimus in the blood, significantly exceeding the maximum recommended. Other factors that increase the risk of this undesirable phenomenon include: availability previous disease heart, the use of corticosteroids, hypertension, renal and hepatic dysfunction, infections, hypervolemia, edema. Patients with tall risk and receiving intensive immunosuppressive therapy, in particular children, before and after transplantation (after 3 and 9-12 months) is necessary carry out echocardiographic and ECG monitoring. If anomalies are revealed, should be to consider The question of reducing the dose of medicines containing tacrolimus, or replacing tacrolimus with another immunosuppressant. Tacrolimus may cause lengthening of the interval QT and a disturbance of the rhythm of the heart such as "pirouette" (bi-directional spindle-shaped ventricular tachycardia). Care should be taken when treating patients with a suspected or diagnosed congenital or acquired syndrome of an elongated interval QT, as well as patients receiving drugs, lengthening interval QT, causing electrolyte disturbances or increasing the concentration (exposure) of tacrolimus in the blood. It should also pay attention to patients with risk factors for lengthening the interval QT, including patients with episodes of lengthening the interval QT in an individual or family anamnesis, congestive heart failure, bradyarrhythmias and electrolyte disorders. The perforation of the gastrointestinal tract was noted in patients treated with tacrolimus. As

the perforation of the gastrointestinal tract is a significant event from a medical point of view,which can lead to a serious or life-threatening condition, after the appearance of signs or symptoms of perforation, it is necessary to immediately begin treatment activities.

Patients treated with tacrolimus may develop post-transplant lymphoproliferative diseases (PTLZ) associated with the Epstein-Barr virus. With simultaneous application of tacrolimus with antilymphocytic antibodies (for example, daclizumab, basiliximab) the risk of PTFE increases. Children under 2 years old, as well as children with a negative test for the capsid antigen of the Epstein-Barr virus, are considered to be at high risk of development of PTLZ. Therefore, prior to the appointment of Prograf® in this group of patients, a serological presence of a capsid antigen of the Epstein-Barr virus. In the process of treatment, it is recommended to carry out careful monitoring for the Epstein-Barr virus by polymerase chain reaction (PCR). Positive PCR for the Epstein-Barr virus can persist for 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, seizures and visual disturbances, it is necessary to conduct a radiological method of investigation, for example, magnetic resonance imaging. When confirming the diagnosis, you need to exercise adequate control over blood pressure and seizures, and immediately terminate the systemic administration of tacrolimus. If these measures are taken, this condition is completely reversible in most patients.

In patients receiving immunosuppressive therapy, including Prograf®, the risk of opportunistic infections (caused by bacteria, fungi, viruses, protozoa) is increased. 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 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 neurological symptoms on the background of immunosuppressive therapy.

Cases have been reported partial red-bladder bone marrow aplasia (PKAA) in patients who received tacrolimus. All patients had risk factors for PKA, such as the presence of parvovirus B19 infection, disease or concomitant therapy associated with the possibility of developing PTCA. Immunosuppressive therapy increases the risk of malignant neoplasms, in particular, malignant skin tumors. It is recommended to limit insolation and ultraviolet radiation, wear appropriate clothing, use sunscreens with a high protection factor.

The risk of developing a secondary cancer is unknown.

Capsules of the preparation Prografcontain lactose, therefore, special care should be taken when prescribing the drug to patients with rare hereditary diseases associated with intolerance to galactose, deficiency of lactase or glucose-galactose malabsorption.

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

Care should be taken when driving vehicles and working with potentially dangerous mechanisms. Tacrolimus can cause visual and neurological disorders, especially in combination with alcohol.

Form release / dosage:

Capsules 0.5 mg, 1 mg, 5 mg.

For 10 capsules in a PVC / aluminum foil blister, 5 blisters in a sealed aluminum bag, along with a packet containing 1 g of silica gel.

For 1 sealed aluminum bag together with instructions for use in a cardboard bundle.

Packaging:(10) - 80-120 bags, blisters (5) - aluminum bags-carton boxes
(10) - blisters (5) - bags, aluminum, packings, cardboard

Storage conditions:

In the original packaging at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

Capsules in aluminum blister pack: 3 years.

After opening the primary package (sealed aluminum bag): 1 year.

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

Terms of leave from pharmacies:On prescription

Registration number:LS-000923

Date of registration:05.04.2011

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®)