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

Name component	Amount, mg
Name component	0.5 mg	1 mg	5 mg
Active substance:
Tacrolimus	0,50	1,00	5,0
(in the form of tacrolimus monohydrate)	(0,51)	(1,02)	(5,1)
Excipients:
Hypromellose	0,15	0,3	1,5
Ethyl cellulose	0,15	0,3	1,5
Lactose Monohydrate	53,64	107,28	536,4
Magnesium stearate	0,55	1,1	5,5
*Capsule shell composition:*
Titanium dioxide (E 171)	0,366	0,716	1,308
Iron Oxide Red Dye Oxide (E 172)	0,010	0,014	0,104
Gelatin	27,496	39,114	98,198
Sodium lauryl sulphate	Footprints	Footprints	Footprints
Composition of ink for the inscription on the capsule (Opacode S-1-15083):
Glaze pharmaceutical 45% (shellac solution in ethanol)			60,700%
Lecithin (Soybean)			0,480%
Simethicone			0,010%
The iron dye red oxide (E 172)			20,000%
Giprolase			0,300%

Description:

Capsules 0.5 mg:

Hard gelatin capsules number 5, on the pale yellow cap of the capsule there is a red inscription "0.5 mg", on the orange capsule case - "647". The contents of the capsules are white powder.

Capsules 1 mg:

Hard gelatin capsules №4, on the white cover of the capsule there is a red inscription "1mg", on the orange capsule case -" 677 ".The contents of the capsules are white powder.

Capsules 5 mg:

Hard gelatin capsules with a size of 0, a red inscription "5 mg" is marked on the grayish-red cap of the capsule, on the orange capsule case - "687". 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. Advagraf®, sustained-release capsules are a dosage form that provides a long-term absorption of tacrolimus in the gastrointestinal tract. The average time to reach C_mOh is about 2 hours.Absorption of tacrolimus is variable (the variability of absorption in adult patients 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 secretion does not affect the absorption of the drug. After reaching the equilibrium concentration of tacrolimus with Advagraf®, there is a high correlation between AUC and minimal (C₀) concentrations of tacrolimus in the blood. Therefore, monitoring of the minimum (C₀) concentrations of tacrolimus in the blood allows you to judge the systemic exposure of the drug.

Distribution and elimination

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 about 20: 1. A significant proportion of plasma tacrolimus (> 98.8%) is in the plasma-bound state (serum albumin, α-1-acid glycoprotein) bound to plasma proteins.

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. 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.

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

Indications:

Prevention and treatment of rejection of liver allograft, kidney 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.

Pregnancy and lactation:

Pregnancy

The results of preclinical studies and studies conducted in humans show that the drug 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, 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).

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 Advagraf® should refrain from breastfeeding.

Dosing and Administration:

Advagraf® is the oral form of tacrolimus for once-daily administration.

Therapy with Advagraf® requires careful monitoring by qualified personnel and with the necessary equipment. 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 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.

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 Advagraf® 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 blood levels (see the section on "Monitoring the therapeutic concentration of tacrolimus in the blood" below).

When clinical signs of rejection appear, consideration should be given to the need for correcting the immunosupplement therapy regimen. 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 (the area under the pharmacokinetic graft PFC₀_-₂₄) when taking Advagraf® was approximately 10% lower compared to the Prograph. The relationship between the minimum levels of tacrolimus (C₂₄) and the system exposure of Advagraf® was the same as when applying the Program.In the transition (conversion) from the Program to Advagraf®, minimum tacrolimus levels should be measured both before conversion from one drug to another, and for the next two weeks. In this case, the dose of Advagraf® should be adjusted to achieve a systemic exposure of tacrolimus similar to the Program.

In patients after kidney and liver transplantation de novo PFC₀_-24 tacrolimus on the first day of application of Advagraf® was accordingly 30% and 50% lower compared to equivalent doses of the Prograph.

By the 4th day the system exposure of tacrolimus, estimated by C₀, in the application of Prograph and Advagraf® in patients after liver and kidney transplant was the same. To ensure adequate exposure of tacrolimus in the treatment of Advagraf® within the first two weeks after transplantation, regular and thorough monitoring of the minimal (C₀) concentration of tacrolimus in the blood. As tacrolimus - a substance with low clearance, to achieve equilibrium concentrations after correction of the dose of Advagraf® may take several days. For patients who can not take the drug orally immediately after transplantation, tacrolimus may be given intravenously (Program 5 mg / ml, infusion concentrate) at a dose of approximately one fifth of the recommended oral dose for this indication.

Mode of application

The oral daily dose of Advagraf® is recommended in the morning once a day. The use of prolonged-action capsules of Advagraf® is carried out 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 are recommended to be washed down with a liquid (preferably water). To achieve maximum absorption, Advagraf® should be taken on an empty stomach: 1 hour or 2-3 hours after eating. 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

Kidney Transplantation

Prevention of graft rejection

Oral therapy with 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.

Liver transplantation

Prevention of graft rejection

Oral therapy with 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.

Dose adjustment in the post-transplant period

With the passage of time after kidney or liver transplantation, the dose of Advagraf® is usually reduced. In some cases, it is possible to cancel the concomitant immunosuppressants, i.e. transition to monotherapy with Advagraf®. Improving the patient's condition can alter the pharmacokinetics of tacrolimus and require additional adjustment of the dosages of Advagraf®.

Treatment of transplant rejection

For the purpose of arresting transplant rejection, the following approaches are recommended: increasing the dose of tacrolimus, increasing corticosteroid therapy, brief courses of mono- / polyclonal antibody therapy. If there are signs of toxicity tacrolimus (eg, expressed unwanted reactions), you may need to reduce the dose of Advagraf®.Information on the transition from cyclosporine to Advagraf® is contained in the section "Conversion (transition) from cyclosporin to Advagraf®."

Kidney and liver transplantation

When switching from other immunosuppressants to Advagraf®, treatment should begin with the initial oral doses described in the sections "Preventing graft rejection" in kidney and liver transplantation.

Heart transplantation

When switching to therapy with 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 organs

Clinical experience with the application of Advagraf® for the treatment of patients after transplantation of the lung, pancreas, intestine is absent. but tacrolimus (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 0.3 mg / kg / day.

Conversion (transition) from cyclosporin to Advagraf®

Care should be taken when switching from cyclosporine to Advagraf®.Treatment with Advagraf® is recommended starting after the determination of the concentrations of cyclosporin in the blood and assessing the clinical state of the patient. Conversion should be postponed if there are elevated levels of cyclosporine to the blood. In practice, tacrolimus therapy begins 12-24 hours after discontinuation of cyclosporine. After the transition, it is recommended to control the levels of cyclosporine in the blood, since it is possible to slow the clearance of cyclosporine.

Conversion (transition) from the Program to Advagraf®

If patients after allotransplant taking Progra twice a day need to be transferred to Advagraf® once a day, the ratio of daily doses during the transition should be 1: 1 (mg: mg). Advagraf® is recommended in the morning. After switching to Advagraf®, it is necessary to monitor the minimum (C₀) concentration of tacrolimus in the blood and adjust the dose of the drug to maintain the systemic exposure of tacrolimus at the same level.

Dose adjustment in selected patient categories

Patients with hepatic dysfunction

In patients with severe hepatic dysfunction to maintain minimal (C₀) concentrations of tacrolimus in the blood within the recommended therapeutic range, a dose reduction of Advagraf® may be required.

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 renal 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 to achieve similar minimum (C₀) concentrations of tacrolimus in the blood may require higher doses of the drug than in patients of the white race.

Floor

Information that men and women require different doses of the drug to achieve equal minimum (C₀) tacrolimus concentrations in the blood are absent.

Elderly patients

Information that elderly patients require special doses of Advagraf® are not available.

Recommendations for monitoring the therapeutic concentration of tacrolimus in the blood

Dose selection should be based on a clinical assessment of individual riskrejection and tolerability of the drug, as well as on the monitoring of the therapeutic level of tacrolimus 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 levels in the blood are controlled primarily by means of immunoassay methods. Correlation between the minimum (C₀, FROM₂₄) concentrations and system exposure (AUC₀_-₂₄) tacrolimus in the blood with the use of both drugs, Advagraf® and Prograf, is the same.

In the post-transplant period, careful monitoring of the minimal (C₀, FROM₂₄) concentrations of tacrolimus in the blood. The minimum concentrations of 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 level of tacrolimus in the blood should be carefully monitored after switching from the Program to Advagraf®, adjusting the doses of the drugs, changing the regimen of immunosuppressive therapy, or with the simultaneous use of 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 Drug Products"). The frequency of monitoring the level of the drug in crocs Since Advagraf® is a low-clearance preparation, it may take several days to reach the equilibrium concentrations of tacrolimus in the blood after correcting the dose of Advagraf®.

According to clinical studies, in most cases, treatment successfully with therapeutic levels 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 level of the drug in the blood is 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.

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.

Adverse events classified by organs and systems are listed below in order of decreasing frequency of detection: very frequent (≥ 1/10), frequent (from ≥ 1/100 to <1/10), infrequent (from ≥ 1/1000 to <1 / 100), rare (from ≥ 1/10 000 to <1/1 000), very rare (<1/10 000), unknown (to establish the frequency of which the data is not enough).

A heart

frequent: ischemic coronary disorders, tachycardia;

infrequent: ventricular arrhythmias and cardiac arrest, heart failure, cardiomyopathies, ventricular hypertrophy, supraventricular arrhythmias, heart palpitations, abnormal ECG parameters, irregular heartbeat and pulse rate and rhythm;

rare: pericardial effusion;

very rare: anomalous indicators of the echocardiogram.

Blood and lymphatic system

frequent: anemia, leukopenia, thrombocytopenia, leukocytosis;

infrequent: coagulopathy, abnormalities in coagulogram, pancytopenia, neutropenia;

rare: thrombotic thrombocytopenic purpura, hypoprothrombinemia.

Nervous system

very frequent: tremor, headache;

frequent: epileptoid seizures, impaired consciousness, paresthesia and dysesthesia, peripheral neuropathies, dizziness, violation of writing, nervous system disorders;

infrequent: coma, hemorrhages in the central nervous system and cerebral circulatory disorders, paralysis and paresis, encephalopathy, speech and articulation disorders, amnesia;

rare: increased muscle tone;

very rare: myasthenia gravis.

Body of sight

frequent: blurred vision, photophobia, eye diseases;

infrequent: cataract rare: blindness.

The organ of hearing and balance

frequent: noise (ringing) in the ears;

infrequent: hearing loss;

rare: neurosensory deafness;

very rare: hearing impairment.

Respiratory system and mediastinum

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

infrequent: respiratory failure, respiratory tract disorders, asthma;

rare: acute respiratory distress syndrome.

Gastrointestinal disorders

very frequent: diarrhea, nausea;

frequent: 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, sensations of bloating and swelling in the abdomen, loose stool, symptoms of disorders of the gastrointestinal tract;

infrequent: paralytic intestinal obstruction (paralytic ileus), peritonitis, acute and chronic pancreatitis, increased level of amylase in the blood, gastroesophageal reflux disease, impaired gastric evacuation function;

rare: subileus, pancreatic pseudocysts.

Kidney, and urinary pathways

very frequent: impaired renal function;

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

infrequent: anuria, hemolytic uremic syndrome;

very rare: nephropathy, hemorrhagic cystitis.

Skin and subcutaneous tissue

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

infrequent: dermatitis, photosensitization;

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

Very rare: Stevens-Johnson syndrome.

Musculoskeletal system and connective tissue

frequent: arthralgia, muscle cramps, pain in the limbs, back pain;

infrequent: articular disorders.

Endocrine system

rare: hirsutism.

Metabolism and nutrition

very frequent: hyperglycemia, diabetes, hyperkalemia;

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

infrequent: dehydration, hypoproteinemia, hyperphosphatemia, hypoglycemia.

The immune system (infection and invasion)

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 therapy with Advagraf.

Injuries, poisonings, complications of procedures

frequent: primary dysfunction of the transplant.

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.

Vascular system

very frequent: hypertension;

frequent: bleeding, thromboembolic and ischemic complications, violation of peripheral circulation, arterial hypotension;

infrequent: heart attack, deep vein thrombosis of the extremities, shock.

General disorders and complications

frequent: asthenia, febrile conditions, swelling, pain and discomfort, increased alkaline phosphatase levels in the blood, increased body weight, impaired body temperature perception;

atypical: 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 in the blood, weight loss;

rare: thirst, loss of balance (fall), a feeling of stiffness in the chest, difficulty moving;

very rare: an increase in the mass of adipose tissue.

Immune system (allergic reactions)

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

Liver and bile ducts

frequent: increased levels of hepatic enzymes, violations of liver function, cholestasis and jaundice, damage to liver cells and hepatitis, cholangitis;

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

very rare: liver failure, stenosis of the bile duct.

Reproductive system and mammary glands

infrequent: dysmenorrhea and uterine bleeding

Fertility

The negative effect of tacrolimus on male fertility, expressed in a decrease in the number and mobility of spermatozoa, was found in rats.

Mental sphere

very often: insomnia;

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

infrequent: psychotic disorders.

Overdose:

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 nitrogen, urea 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

After oral administration tacrolimus is metabolized in the intestinal cytochrome system CYP3A4. Simultaneous reception of drugs or medicinal herbs with established inhibitory or inducing action on CYP3A4 can respectively increase or decrease the concentration of tacrolimus in the blood. Therefore, in order to maintain adequate and constant exposure of tacrolimus, it is recommended to monitor the concentration of tacrolimus in the blood and, if necessary, adjust the dose of Advagraf®.

Inhibitors of Metabolism

Based on clinical experience,that the concentration of tacrolimus in the blood can significantly increase the following drugs: antifungal agents (ketoconazole, fluconazole, itraconazole, voriconazole), macrolide antibiotics (erythromycin), HIV protease inhibitors (ritonavir). When prescribing these drugs with tacrolimus, you may need to reduce the dose of Advagraf®.

Pharmacokinetic studies have shown that an increase in tacrolimus 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 of 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, 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, norethindrone, quinidine, tamoxifen, (triacetyl) oleandomycin.

It is also 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-mediated metabolism of tacrolimus and increase its concentration in the blood.

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, an increase in the dose of Advagraf® 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 the half-life of phenobarbital and antipyrine.

Other potential interactions that increase the systemic exposure of tacrolimus

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

Other Potential Adverse Drug Interactions

The simultaneous use of tacrolimus with drugs that have nephro- or neurotoxicity (eg, aminoglycosides, inhibitors of gyrase, 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. It should be taken into account the possible competitive interaction of tacrolimus with drugs,possessing high affinity for blood plasma proteins (nonsteroidal anti-inflammatory drugs, oral anticoagulants, oral antidiabetics).

Incompatibility

Tacrolimus is incompatible with polyvinyl chloride (PVC). The tubes, syringes and other equipment used to prepare the suspension from the capsules of Advagraf® should not contain PVC.

Special instructions:

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. Clinical data on the use of Advagraf® in acute rejection refractory to other immunosuppressant therapy in adult patients are not available.

Currently there is no clinical data on the use of Advagraf® in order to prevent graft rejection during cardiac transplantation and in childhood.

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),indicators of hepatic and renal function, hematologic indices, coagulogram, level of proteinemia. In the presence of clinically significant changes, correction of immunosuppressive therapy is necessary.

When applying Advagraf®, the administration of herbal preparations containing St. John's Wort should be avoided (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 Advagraf®.

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 (see section "Conversion (transition) from cyclosporin to Advagraf®").

Cases of ventricular hypertrophy or cardiac hypertrophy reported as cardiomyopathy have rarely been observed in patients taking Prograph and are therefore possible with the treatment of Advagraf®.In most cases, myocardial hypertrophy was reversible and was observed at concentrations (C₀) 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 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 Advagraf® or replacing the drug with another immunosuppressant.

Tacrolimus may cause lengthening of the interval QT, while violations of the rhythm of the heart such as "pirouette" (bi-directional 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. There is also evidence of an increased risk of PTFE in patients with the Epstein-Barr virus capsid antigen. Therefore, prior to the appointment of Advagraf®, serological testing for the presence of the Epstein-Barr virus capsid antigen should be performed in this group of patients. 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.

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 the progressive multifocal leukoencephalopathy (PML) associated with JC virus. 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 conducting a differential diagnosis in patients with signs of impaired renal function or neurological symptoms on the background of immunosuppressive therapy.

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.

The risk of developing a secondary cancer is unknown.

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.

Since the capsules of the long-acting Advagraf® contain lactose, special care should be taken when prescribing the drug to patients with rare hereditary diseases associated with galactose intolerance, Lappease lactase deficiency (Lapp) or glucose-galactose malabsorption.

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

Tacrolimus can cause visual and neurological disorders, especially in the combination of Advagraf® with alcohol.

Form release / dosage:Capsules of prolonged action, 0.5 mg, 1 mg and 5 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.

For 1 sealed aluminum bag along with instructions for use in a cardboard box.

Storage conditions:

Store in the original packaging, at a temperature not higher than 25 ° C in a place inaccessible to children.

Shelf life:

3 years.

After opening the aluminum bag: 1 year.

The drug should not be used after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LSR-006205/09

Date of registration:31.07.2009 / 23.09.2016

Expiration Date:Unlimited

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

Manufacturer: & nbsp

ASTELLAS Ireland, Co.Ltd. Ireland

ORTAT, CJSC Russia

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

Information update date: & nbsp08.02.2017

Illustrated instructions

Instructions

Advagraf® (Advagraf®)