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

Active substance: Gacrolimus 3.0 mg (in the form of tacrolimus monohydrate - 3.06 mg); Excipients: hypromellose - 0.9 mg; ethyl cellulose - 0.9 mg; lactose monohydrate - 321.84 mg; magnesium stearate - 3.3 mg; composition of the capsule shell: titanium dioxide (EI71) 1.060 mg; ferric iron oxide yellow (E172) - 0.500 mg; ferric dye oxide red (E172) - 0.046 mg; gelatin - 75,394 mg; sodium lauryl sulfate - traces; composition of the inscription on the capsule (Opacode S-1-15083): glaze pharmaceutical 45% (shellac solution in ethanol) - 60,700%; lecithin (soybean) - 0.480%; simicop - 0.010%; iron dye oxide red (E172) - 20,000%; giprolose - 0.300%.

Description:Hard gelatin capsules, on the orange capsule cover there is a red inscription "3 mg & quot ;, on the orange shell of the capsule - 637. The contents of the capsules are a white powder.

Pharmacotherapeutic group:immunodressiressnos means - calcineurin inhibitor

Pharmacodynamics:

At the molecular level, effects and intracellular cumulation of tacrolimus are due to binding to the cytosolic protein (FKI3P 12). Complex FKBP 12-tacrolimus specifically and competently inhibits calcineprin, providing calcium-dependent blocking of T-cell signaling pathways and preventing the 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:

Suction

It is established that in the human body tacrolimus quickly absorbed in the gastrointestinal tract. Advagraf®, prolonged-action capsules is a dosage form that provides a long-term absorption of tacrolimus in the gastrointestinal tract. The mean time to reach the maximum concentration (C_max) is about 2 hours. Absorption of tacrolimus is variable (absorption variability in adult patients is 6-43%). Bioavailability of tacrolimus when administered in the form of capsules averages 20-25%. Bioavailability, as well as the rate and extent of absorption of tacrolimus with simultaneous intake with food are reduced. The nature of bile excretion does not affect the absorption of the drug. After reaching the equilibrium concentration of tacrolimus at admissionThe drug Advagraf * shows a high correlation between the area under the pharmacokinetic curve (AUC) and the minimum (Co) concentrations of tacrolimus in the blood. Therefore, monitoring the minimum (Co) concentrations of tacrolimus in the blood allows you to judge the systemic exposure of the drug.

Distribution

The distribution of tacrolimus in the human body after intravenous administration is biphasic. 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 fraction of plasma tacrolimus (> 98.8%) is in the state bound to plasma proteins (serum albumin, a-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.

Metabolism

Tacrolimus is actively metabolized in the liver, mainly through the isoenzyme CYP3A4 cytochrome IM50. Metabolism tacrolimus also intensively flows in the intestinal wall. Several metabolites of tacrolimus have been identified.In vitro experiments, 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

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. Low hematocrit and hypoproteinemia contribute to an increase in the unbound fraction of tacrolimus, accelerating the clearance of tacrolimus. Glucocorticosteroids used in transplantation can also increase the intensity of metabolism and accelerate the clearance of tacrolimus.

Tacrolimus semi-vascular period is long and variable. In healthy people, the average half-life in whole blood is approximately 43 hours.

After intravenous and oral administration ¹⁴T-labeled tacrolimus, the major portion of radioactivity was found in feces. Approximately 2% of radioactivity was recorded in urine. In urine and feces less than 1% of tacrolimus was determined unchanged. Consequently, tacrolimus Before elimination, it was almost completely mstabilized: the main way of elimination was bile.

Indications:

Prevention of rejection of liver or kidney allografts in adult patients.

Treatment of allograft rejection, resistant to standard regimens of immunosuppressive therapy in adult patients.

Contraindications:

Hypersensitivity to tacrolimus, other macrolides or any of the excipients. Lactase deficiency, lactose intolerance, glucose galactose malabsorption.

Carefully:

Pregnancy and lactation:

Pregnancy

The results of preclinical studies and studies conducted in humans 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 reactions andnegative effect of the drug on the course and outcome of pregnancy 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 sufficiently established, the drug is taken during pregnancy only if there is no safer alternative and only when 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). There are reports of premature (<37 weeks) births (66 of 123 (53.7%)) of newborns; most of the newborns had a normal body weight for their gestational age), as well as cases of spontaneously resolved hyperkalemia in newborns (8 of 111 (7.2%) of newborns).

In rats and rabbits tacrolimus had embryotoxic and phenotoxic effects in doses that are toxic to the mother's body.

Breastfeeding 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 Advagraf® should refrain from breastfeeding.

Dosing and Administration:

Advagraf® is the oral form of tacrolimus for once-daily administration. Therapy with the drug Advagraf requires careful monitoring by personnel with the appropriate qualifications and having the necessary equipment at their disposal. This drug can be prescribed only 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-action capsules) is unsafe. This can lead to rejection of the transplant or an increased 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.

The initial doses presented below should only be considered as recommendations. In the initial postoperative period, Advagraf® 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 the drug "Advagraf®" 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 "Recommendations for monitoring therapeutic concentration of tacrolimus in the blood" below).

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

In patients after kidney and liver transplantation de novo PFC0-24 tacrolimus on the first day of application of the preparation Advagraf® was accordingly 30% and 50% lower compared to equivalent doses of Prograph. By the 4th day the system exposure of tacrolimus, estimated by Co, with the use of Program and Advagraf® in patients after liver and kidney transplantation was the same. In order to ensure adequate exposure of tacrolimus in the treatment with the drug Advagraf®, regular and careful monitoring of the minimum (Co) concentration of tacrolimus in the blood is recommended during the first two weeks after transplantation. As tacrolimus - a substance with low clearance, it may take several days to reach equilibrium concentrations after correcting the dose of the drug.

For patients who can not take the drug orally immediately after transplantation, tacrolimus may be administered intravenously (Prograf® 5 mg / ml, concentrate for the preparation of a solution for intravenous administration) at a dose of approximately one fifth of the recommended oral dose for this indication.

Mode of application

The oral daily dose of the drug Advagraf® is recommended in the morning once a day.Taking capsules of the drug Advagraf® prolonged action immediately after they are removed from the blister. Patients should be warned about the presence of a desiccant in the package (a bag of silica gel), which is not intended for admission. Capsules must be taken whole, washed down with liquid (preferably water). To achieve maximum absorption of the drug Advagraf® is recommended to be taken on an empty stomach: for 1 hour or 2-3 hours after taking the beggar. The missed dose should be taken as soon as possible, preferably the same day; Do not take a double dose the next morning.

Duration of the drug

To prevent rejection of the graft, the state of immunosuppression must be maintained constantly; therefore, the duration of therapy is not limited.

Dosing recommendations

Prophylaxis of rejection after kidney transplantation

Oral therapy with the drug Advagraf® should be started at a daily dose of 0.20-0.30 mg / kg, once a day in the morning. The drug should be taken within 24 hours after transplantation. With the passage of time after transplantation, the dose of Advagraft® is usually reduced.In some cases, it is possible to cancel the concomitant immunosuppressants, that is, the transition to monotherapy with the drug Advagraf®. Improvement of the patient's condition can change the pharmacokinetics of tacrolimus and require additional adjustment of the doses of the preparation of Advagraf®.

PProphylaxis of rejection after liver transplantation

Oral therapy with the drug Advagraf® should be started at a daily dose of 0.10-0.20 mg / kg, once a day in the morning. The drug should be taken 12-18 hours after transplantation. With the passage of time after transplantation, the dose of Advagraft® is usually reduced. In some cases, it is possible to cancel the concomitant immunosuppressants, i.e. the transition to ionotherapy with the drug Advagraf®. Improvement of the patient's condition can change the pharmacokinetics of tacrolimus and require additional adjustment of the doses of the preparation of Advagraf®.

Conversion (transition) from the Program to the Advagraf

If patients after allotransplant taking Progra twice a day, should be transferred to the drug Advagraf once a day, the ratio of daily doses during the transfer should be 1: 1 (mg: mg).Advagraf® is recommended in the morning.

In stable patients transferred from Prograf (twice daily intake) to Advagraf® (once daily intake), with a total daily dose of 1:1 (mg: mg), systemic exposure of tacrolimus (area under the pharmacokinetic curve of PFC0.24) when taking Advagraf® was approximately 10% lower compared to the Prograph. The relationship between the minimum concentrations of tacrolimus (C24) and the system exposure of the drug Advagraf® was the same as when applying Prograph. In the transition (conversion) from the Program to Advagraf®, minimum concentrations of tacrolimus should be measured both before conversion from one drug to another, and during the next two weeks. In this case, the dose of the drug Advagraf® should be adjusted to achieve a systemic exposure of tacrolimus similar to the Program.

Conversion (conversion) from cyclosporin to Advagrack

Care should be taken when switching from cyclosporine to Advagraf®. Simultaneous use of cyclosporine and tacrolimus ns is recommended. Treatment with the drug Advagraf® is recommended to begin after the determination of the concentrations of cyclosporin in the blood and evaluation of the clinical condition of the patient.Conversion should be postponed in the presence of elevated concentrations of cyclosporine to the blood. In practice, tacrolimus therapy begins 12-24 hours after discontinuation of cyclosporine. After the transition, it is recommended to monitor the concentration of cyclosporin in the blood, since it is possible to slow the clearance of cyclosporine.

Legraft rejection

In order to stop graft rejection, the following approaches are recommended: increasing tacrolimus dose, increasing glucocorticosteroid therapy, brief courses of mono- / polyclonal antibody therapy. If there are signs of toxicity of tacrolimus (for example, severe undesirable reactions), it may be necessary to reduce the doses of the drug Advagraf®.

Kidney Transplantation or liver

When transferring from other immunosuppressants to Advagraf®, treatment should begin with the initial oral doses described in the sections on prevention of rejection in kidney or liver transplantation.

Heart transplantation

When switching to therapy with the drug Advagraf® in adult patients, the initial oral daily dose of the drug is 0.15 mg / kg, once a day in the morning.

Transplantation of other organon

Clinical experience of using the drug Advagraf® for the treatment of patients after a transplantation of the lung, pancreas, intestine is absent. However, gacrolimus (Prograf) is used in patients with lung transplants in the initial oral dose of 0.10-0.15 mg / kg / day, after pancreas transplantation in the initial oral dose of 0.2 mg / kg / day, after intestinal grafting in the initial oral dose of 0.3 mg / kg / day.

Recommendations for monitoring therapeutic concentration of tacrolimus at blood

The choice of doses should be based on a clinical assessment of the individual risk of rejection and drug tolerability, as well as on the monitoring of tacrolimus concentration in the blood.

To select the optimal dose, several methods are used to determine the concentration of tacrolimus in whole blood. Comparison of monitoring results published in the literature with monitoring results in a separate clinic should be performed taking into account the method used to determine the concentration of blood tacrolimus. In modern clinical practice, tacrolimus concentrations in the blood are controlled predominantly by immunoassay methods.

Correlation between the minimum (C₍₎, FROM24) concentrations and systemic exposure (AUC 0.24) tacrolimus in the blood in the application of both drugs. Advagraf® and Prograf are the same.

In the post-transplant period, careful monitoring of minimal (Co, C24) concentrations of tacrolimus in the blood. The minimum concentration of the drug Advagraf® in the blood should be determined approximately 24 hours after taking the drug, before taking the next dose. In the first two weeks after transplantation, more frequent monitoring of the minimum concentration is recommended, then periodic monitoring is performed during the maintenance period. The therapeutic concentration of tacrolimus in the blood should be carefully monitored after switching from the Program to Advagraf®, adjusting the doses of the drugs, changing the immunosuppressive regimen or by using drugs that can cause changes in tacrolimus concentrations in the blood (see "Conversion (transition) from cyclosporine to Advagraf®, "" Conversion (transition) from the Program to Advagraf® "and" Interaction with other medicinal products "). The frequency of monitoring the concentration of the drug in the blood is determined by clinical necessity.Since Advagraf® is a low-clearance preparation, it may take several days to adjust the equilibrium concentrations of tacrolimus in the blood after adjusting the dose of Advagraf.

According to clinical studies, in most cases, treatment successfully with therapeutic concentrations of tacrolimus in the blood does not exceed 20 ng / ml. When interpreting the therapeutic concentration of tacrolimus in the blood, the patient's clinical condition must be taken into account.

According to available data, in the initial post-transplant period in patients after liver transplantation the therapeutic concentrations of the drug in the blood are in the range of 5-20 ng / ml, and after kidney or heart transplantation - 10-20 ng / ml. During maintenance immunosuppressive therapy in patients after a liver, kidney or heart transplant, drug concentrations in the blood are usually in the range of 5-15 ng / ml.

Dose adjustment in selected patient categories Patients with hepatic dysfunction

In patients with severe hepatic dysfunction, a dose reduction with Advagraf® may be required to maintain the minimum (Co) concentration of tacrolimus in the blood within the recommended therapeutic range.

Patients with renal dysfunction

Since renal function does not affect the pharmacokinetics of tacrolimus, there is no need to adjust doses. However, due to the nephrotoxic potential of tacrolimus, it is recommended that the kidney function be carefully monitored (including determination of serum creatinine concentration, calculation of creatinine clearance, and control over the amount of urine released).

Race

In black patients, in order to achieve similar minimum (Co) concentrations of tacrolimus in the blood, higher doses of the drug may be required than in patients of the white race.

Floor

Information that men and women require different doses of the drug to achieve equal minimum (Co) concentrations of tacrolimus in the blood are absent.

Elderly patients

Information about the fact that elderly patients require special doses of the drug Advagraf® are not available.

Children

Recommendations for dosing the drug for children under 18 are not available due to limited clinical experience.

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.

The most frequent undesirable reactions (noted in > 10% of patients): tremor, kidney failure, hyperglycemia, diabetes mellitus, gyerculomyemia, infections, hypertension and insomnia.

Many of the undesirable reactions presented below are reversible and / or reduced with a lower dose. Undesirable reactions classified by organs and systems are listed below in descending order of frequency of detection: very often (> 1/10), often (from > 1/100 to <1/10), infrequently (from > 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). Within each frequency group, undesirable phenomena are presented in descending order of severity.

Infectious and parasitic diseases

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

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

Patients receiving immunosuppressive therapy have a higher risk of malignant tumors. In the application of tacrolimus, both benign and malignant neoplasms, including the Epstein-Barr virus, are associated with lymphoproliferative diseases and skin cancer.

Violations of the blood and lymphatic system

often: anemia, thrombocytopenia, leukopenia, abnormalities in the analysis of erythrocytes, leukocytosis

infrequently: coagulopathy, pancytopenia, neutropenia, deviations in coagulogram indices

rarely: thrombotic thrombocytopenic purpura, hypoprothrombinsmia

frequency unknown: partial red cell aplasia, agranulocytosis, hemolytic anemia

Immune system disorders

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

Disorders from the endocrine system

rarely: hirsutism

Disorders from the metabolism and nutrition

very often: diabetes mellitus, hyperglycemia, hyperkalemia

often: anorexia, metabolic acidosis, electrolyte disorders, hyponatremia, hypervolemia, hyperuricemia, giomagniemia, hypokalemia, hypocalcemia, decreased appetite, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, hypophosphatemia

infrequently: dehydration, hypoglycemia, hypoproteinemia, hyperphosphataemia

Disorders of the psyche

very often: insomnia

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

infrequently: psychotic disorders

Disturbances from the nervous system

very often: headache, tremor

often: disorders of the nervous system, convulsions, impaired consciousness, peripheral neuropathies, dizziness, paresthesia and dysesthesia, infringement of the letter infrequently: encephalopathy, hemorrhages in the central nervous system and cerebral circulatory disorders, coma, speech and articulation disorders, paralysis and paresis, amnesia

rarely: increased muscle tone

very rarely: myasthenia gravis

Disturbances on the part of the organ of sight

often: impaired vision, blurred vision, photophobia

infrequently: cataract

rarely: blindness

Hearing disorders and labyrinthine disorders

often: ringing in the ears

infrequently: hearing loss

rarely: sensorineal deafness

very rarely: hearing impairment

Heart Disease

often: ischemic coronary disorders, tachycardia

infrequently: heart failure, ventricular arrhythmias and cardiac arrest, supraventricular arrhythmias, cardiomyopathies, abnormal ECG changes, ventricular hypertrophy, heart palpitations, heart rate and pulse irregularities rarely: pericardial effusion

very rare: prolongation of the QT interval on the ECG, ventricular tachysystolic fluke of the pirouette type, pathological changes on the echocardiogram Vascular disorders are very common: hypertension

often: thromboembolic and ischemic complications, vascular hypotension, bleeding, peripheral circulatory disturbances infrequently: deep vein thrombosis of the extremities, shock, infarction

Disturbances from the respiratory system, chest and mediastinal organs

often: pulmonary parenchymal disorders, dyspnea, pleural effusion, cough, pharyngitis,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: symptoms of gastrointestinal disorders, vomiting, gastrointestinal and abdominal pain, inflammatory diseases of the gastrointestinal tract, gastrointestinal bleeding, gastrointestinal ulcers and perforations, ascites, stomatitis and ulceration of the oral mucosa, constipation , dyspepsia, flatulence, feelings of bloating and swelling in the abdomen, loose stools

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

rarely: pancreatic pseudocysts, subillus

Disorders from the liver and bile ducts

very often: abnormal changes in functional liver tests

often: disorders of the biliary tract, damage to liver cells and hepatitis, cholestasis and jaundice

rarely: obliterating endophlebitis of hepatic veins, hepatic artery thrombosis

very rarely: liver failure

Disturbances from the skin and subcutaneous tissues

often: itching, rash, alopecia, acne, hyperhidrosis

infrequent: dermatitis, photosensitivity

rarely: toxic epidermal necrolysis (Lysyll's syndrome)

very rarely: Stevens-Johnson syndrome

Disturbances from musculoskeletal and connective tissue

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

infrequently: articular disorders

Disorders from the kidneys and urinary tract

very common: impaired renal function

often: renal failure, acute renal failure, toxic

nephropathy, acute tubular necrosis, urinary tract damage, oligurnia, disorders of the bladder and urethra

infrequently: hemolytic uremic syndrome, anuria

very rarely: nephropathy, hemorrhagic cystitis

Violations of the genitals and mammary gland

infrequently: dysmenorrhea and uterine bleeding

General disorders and disorders at the site of administration

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

infrequently: weight loss, flu-like syndrome, increased lactate dehydrogenase activity in the blood, feelings of anxiety, poor health, multiple organ failure, a feeling of squeezing in the chest, impaired perception of the temperature of the environment

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

very rarely: increase in fat mass

Trauma, intoxication and complications of manipulation

often: primary transplant dysfunction

Errors in the appointment and dispensing of tacrolimus drugs, including random, unreasonable or uncontrolled replacement of one drug form of tacrolimus for another, and recorded cases of graft rejection (according to available data, the frequency can not be estimated) were noted.

Overdose:

Symptoms

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

Treatment

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:

Tacrolimus, located in the systemic circulation, is metabolized by hepatic cytochrome CYP3A4. When taken orally tacrolimus is also metabolized in the intestinal cytochrome CYP3A4 system.

Simultaneous administration of drugs or medicinal herbs with established inhibitory or inducing action on CYP3A4 may accordingly increase or decrease the concentration of tacrolimus in the blood.

To maintain an adequate and permanent exposure of tacrolimus when used simultaneously 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 Advagraf®. You should also pay attention to the kidney 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 drugs: antifungal agents (kstokonazol, 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, you may need to reduce the dose of the drug "Advagraf®" in almost all patients. Pharmacokinetic studies have shown that an increase in tacrolimus concentrations in the blood is primarily a consequence of an increase in the oral bioavailability of the drug caused by inhibition of intestinal metabolism of tacrolimus. Suppression
The hepatic metabolism of tacrolimus plays a secondary role.

Less pronounced drug interaction was observed with simultaneous application of tacrolimus with clotrimazole, clarithromycin, josamycin, nifedipine, nicardipine, dntiazem, verapamil, amiodarone, danazol, ethinyl estradiol, omeprazole and isfazodom.

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

It is recommended to avoid grapefruit juice in connection with the possibility of increasing the concentrations of tacrolimus in the blood. Lansonrazole and ciclosporin can potentially inhibit SURCA4-mediated metabolism of tacrolimus and increase its concentration in the blood.

Other potential interactions that increase the systemic exposure of tacrolimus

Tacrolimus actively binds to blood plasma proteins. It should be taken into account the possible competitive interaction of tacrolimus with drugs that have a high affinity for plasma proteins (nonstroicanti-inflammatory drugs, oral anticoagulants, oral antidiabetics). Prokinetic means (metoclopramide, cisapride). Cimetidine. Magnesium and aluminum hydroxide.

Inductors metabolism

Based on clinical experience, it was found that the concentration of tacrolimus in the blood can significantly reduce the following drugs: rifampicin, phenytoin, St. John's wort (Hypericum perforatum). When prescribing these drugs with tacrolimus, you may need to increase the dose of the drug "Advagraf®" in almost all patients.

Clinically significant interactions were observed with phenobarbital. Glucocorticosteroids 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 tacrolimus concentrations in the blood.

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

Effect of tacrolimus on metabolism other medicines Tacrolimus inhibits CYP3A4 and with simultaneous admission can have an effect on drugs that are mstabilized in the system CYP3A4. The period of nil elimination of cyclosporin with simultaneous application with tacrolimus is increased. Sicergic / additive effromicro toxic effects can also be observed. 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 concentration 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 the articles 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 period of zero-elimination of phenobarbital and phenazone.

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, gancclovir, acyclovir) can enhance these effects.

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

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

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.

Incompatibility

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

Special instructions:

In practice, there were errors associated with accidental, unintentional or uncontrolled replacement of a prolonged dosage form or immediate-release dosage form. This led to serious adverse reactions, including rejection of the graft,or other undesirable reactions that could be a consequence of a decrease or increase in the area under the pharmacokinetic curve (exposure) of tacrolimus. The patient should take only one of the medicinal 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.

Due to the limited amount of clinical data on the efficacy and safety of the drug Ldvagraf^®It is not recommended to use in patients with childhood (under 18 years) age.

Clinical data on the use of the drug Ldvagraf with resistance to standard regimens of immunosuppressive therapy of rejection in adult patients, as well as for the prevention of rejection in adult patients with a transplanted heart are absent.

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

With the simultaneous use with tacrolimus other drugs, especially strong inhibitors CYP3A4 (teltoprsvir, bocenreviros, ritonavir, ketoconazole, voriconazole, itraconazole, tsethromycin, clarithromycin) or inductors CYP3A4 (rifampicin, rifabutin), it is necessary to take into account the risk of drug interactions and control the concentration of tacrolimus in the blood in order to maintain the target values.

When using the drug Ldvagraf®, the use of herbal preparations containing St. John's wort (Hypericum perforatum), due to the risk of drug interaction leading to both a decrease in tacrolimus concentration in the blood, and an adverse effect on the therapeutic effect of the drug Advagraf®.

Simultaneous use of cyclosporine and tacrolimus should be avoided, and caution should be exercised when treating tacrolimus patients who previously received ciclosporin (see section "Conversion (transition) from cyclosporin to Advagraf®.").

Do not use potassium drugs in high doses, as well as potassium-sparing diuretics.

The simultaneous use of tacrolimus with drugs that have known nephrotoxic or neurotoxic effects may lead to an increase in these effects.

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.

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

Cardiological disorders

Cases of ventricular hypertrophy or cardiac hypertrophy reported as cardiomyopathy were rare but were observed in patients taking Prograf and therefore are possible with the treatment with the drug Advagraf®. 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 glucocorticosteroids, hypertension, impaired renal and hepatic function, infections, hypervolvia, edema.Patients with high risk and receiving intensive immunosuppressive therapy before and after transplantation (after 3 and 9-12 months) should carry out echocardiographic and ECG monitoring. If anomalies are detected, consideration should be given to reducing the dose of the drug Advagraf® or replacing the drug with another immunosuppressant. Tacrolimus may cause lengthening of the interval QT. but at present there is evidence that tacrolimus led to a violation of the rhythm of the heart such as "pirouette" (bi-directional spindle-shaped ventricular tachycardia) is not enough. In the treatment of patients with diagnosed congenital syndrome of an elongated interval QT or suspicion of such a condition should be very careful.

Lymphoproliferative diseases and malignant neoplasms.

Patients treated with tacrolimus may develop post-transplant lymphoproliferative diseases (GGGLZ) associated with the Epstein-Barr virus. With the simultaneous use of the drug with aililfotsitarnymi antibodies (for example, daclizumab, basiliximab) the risk of PTFE increases.There is also evidence of an increased risk of developing PTFE in patients with a negative test for the capsid antigen of the Epstein-Barr virus. Therefore, before the appointment of the drug Advagraf® in this group of patients, a serological test should be performed for the presence of the Epstein-Barr virus capsid antigen. In the course of treatment, it is recommended to carry out careful monitoring for the Epstein-Barr virus using a polymerase valuable reaction (PCR). Positive PCR for the Epstein-Barr virus can persist for months and itself is not evidence of PTLZ or lymphoma.

The risk of developing a secondary cancer is unknown.

Immunosuppressive therapy increases the risk of malignant neoplasms. It is recommended to limit insolation and ultraviolet radiation, wear appropriate clothing, use sunscreens with a high protection factor.

In patients receiving immunosuppressive therapy, including Advagraf®, the risk of opportunistic infections (caused by bacteria, fungi, viruses, protozoa) is increased. Among these infections, nephropathy associated with BV-virus is noted, as well as associated with JC-virus progressive multifocal leukoencephalopathy (NML). Such infections are often associated with deep suppression of the immune system and can lead to severe or fatal outcomes, which must be taken into account when making a differential diagnosis in patients with signs of impaired renal function or neurological symptoms with immunosuppressive therapy.

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.

Partial red cell aplasia.

Cases of partial red cell aplasia (PKAA) were noted in patients taking tacrolimus. In all cases, the presence of such risk factors for PACT as an infection caused by parvovirus B19, contributing to PACA disease or simultaneous administration of drugs associated with PKA was reported.

Specials populations patients.

The experience of treatment of patients not belonging to the white race, as well as patients with high immunological risk (ie, with repeated transplantation, high titer of panel reactive antibodies [PRA]) is limited.

In patients with severe hepatic insufficiency, a dose reduction may be required.

Excipients. Since capsules of the drug Advagraf® of prolonged action contain lactose, special care should be taken when prescribing the drug to patients with rare hereditary diseases associated with intolerance to galactose, deficiency of lactase Lappa (Lapp) or glucosogalactose malabsorption.

Ink for labeling capsules of the preparation Advagraf® contain soy lecithin. Before using the drug Advagraf^® in patients who are hypersensitive to peanuts or soybeans, the risk and severity of hypersensitivity must be compared with the benefit of using the drug.

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

Tacrolimus can cause visual and neurological disorders, especially in combination with alcohol.

Studies on the effect of tacrolimuea (Advagraf®) on the ability to drive vehicles and work with mechanisms were conducted.

Form release / dosage:

Capsules of prolonged action 3 mg.

Packaging:

10 capsules in a PVC / aluminum foil blister, 5 blisters each in a sealed aluminum bag together with a bag of silica gel.

According to the I sealed aluminum bag, along with instructions for use, a cardboard pack.

Storage conditions:

Store in the original packaging at a temperature of ns above 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

After opening the aluminum bag: 3 months.

The drug should be used after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002959

Date of registration:16.04.2015/30.08.2016

Expiration Date:16.04.2020

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: & nbsp23.01.2017

Illustrated instructions

Instructions

Advagraf® (Advagraf®)