Advagraf sustained release capsules 5mg, 50pcs

Composition

1 capsule of prolonged action contains: active ingredient – tacrolimus (in the form of tacrolimus monohydrate) – 0.5 mg,1 mg or 5 mg;excipients – hypromellose, ethylcellulose, lactose monohydrate, magnesium stearate;capsule shell: titanium dioxide (E 171), iron oxide yellow dye (E 172), iron oxide red dye (E 172), gelatin, sodium lauryl sulfate; inscription on the capsule (Opacode S-1-15083): pharmaceutical glaze 45% (shellac solution in ethanol), lecithin (soy), simethicone, iron oxide red dye (E 172), giprolose.

Pharmacological action

Pharmacotherapeutic group: immunosuppressive agent

ATX code: [L04AD02]

Pharmacological properties

Pharmacodynamics At the molecular level, the effects and intracellular accumulation of tacrolimus are due to binding to the cytosolic protein (FKBP 12). The FKBP12-tacrolimus complex specifically and competitively inhibits calcineurin, providing calcium-dependent blocking of T-cell signaling pathways and preventing transcription of a discrete set of lymphokine genes.

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

Pharmacokinetics

Absorption rate

It has been established that tacrolimus is rapidly absorbed in the gastrointestinal tract in humans. Advagraf, long-acting capsules – a dosage form that provides long-term absorption of tacrolimus in the gastrointestinal tract.

The average time to reach Cmax is about 2 hours. The absorption of tacrolimus is variable (the absorption variability in adult patients is 6-43%). The bioavailability of tacrolimus when taken orally in the form of capsules is on average 20-25%. The bioavailability, as well as the rate and degree of absorption of tacrolimus, are reduced when taken simultaneously with food.

The nature of bile excretion does not affect the absorption of the drug. After reaching the equilibrium concentration of tacrolimus when taking Advagraf, there is a high correlation between AUC and minimum (C0) concentrations of tacrolimus in the blood. Therefore, monitoring of the minimum (From 0) concentrations of tacrolimus in the blood allows us to judge the systemic exposure of the drug.

Distribution and elimination

The distribution of tacrolimus in the human body after intravenous use is biphasic. Tacrolimus binds well to red blood cells in the systemic circulation. The ratio of tacrolimus concentrations in whole blood and plasma is ≈ 20: 1. A significant proportion of plasma tacrolimus (>98.8%) is bound to plasma proteins (serum albumin, α-1-acid glycoprotein). Tacrolimus is widely distributed in the body. The steady-state volume of distribution, taking into account plasma concentrations, is about 1,300 liters (in healthy people). The same indicator calculated for whole blood is on average 47.6 liters.

Tacrolimus is a low-clearance substance. In healthy people, the average total clearance calculated from whole blood concentrations is 2.25 l / h. In adult patients after liver, kidney, and heart transplantation, clearance values were 4.1 l / hr,6.7 l / hr, and 3.9 l/hr, 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 elimination half-life of tacrolimus is long and variable. In healthy people, the average elimination half-life in whole blood is approximately 43 hours.

Metabolism and biotransformation

Tacrolimus is extensively metabolized in the liver, mainly by cytochrome P450 CYP3A4. The metabolism of tacrolimus is intense in the intestinal wall. Several metabolites of tacrolimus have been identified. In vitro experiments have shown that only one of the metabolites has an immunosuppressive activity close to that of tacrolimus.

Other metabolites were characterized by weak or no immunosuppressive activity. Only one of the metabolites of tacrolimus was detected in the systemic circulation at low concentrations. Thus, the pharmacological activity of the drug is practically independent of the metabolites.

Excretion

After intravenous and oral use of 14C-labeled tacrolimus, the majority of radioactivity was detected in feces. Approximately 2% of radioactivity was detected in the urine. In urine and faeces, about 1% of tacrolimus was detected unchanged. Consequently, tacrolimus was almost completely metabolized before elimination: bile was the main route of elimination.

Indications

Prevention and treatment of liver and kidney allograft rejection in adult patients. Treatment of allograft rejection resistant to standard immunosuppressive therapy regimens in adult patients.

Use during pregnancy and lactation

Pregnancy:  the results of preclinical and clinical studies show that the drug can pass through the placenta. Preterm birth has been reported (

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 breast-feeding.

Contraindications

Hypersensitivity to the components of the drug.

Side effects

Due to the peculiarities of the underlying disease and the large number of drugs used simultaneously after transplantation, the profile of adverse events of immunosuppressants is difficult to accurately establish. Many of the adverse events described below are reversible and / or lessen with dose reduction. Within each frequency group, adverse events are presented in descending order of severity.

Adverse events classified by organ and system are listed below in descending order of frequency of detection:

• Very often – > 1/10. >
• Often-from ≥1/100 to
• Infrequently-from ≥1/1000 to
• Rarely-from ≥1/10000 to
• Very rare —
• Unknown (for which there is insufficient data to determine the frequency).

Heart:  often — ischemic coronary disorders, tachycardia; infrequently-ventricular arrhythmias and cardiac arrest, heart failure, cardiomyopathy, ventricular hypertrophy, supraventricular arrhythmias, rapid heartbeat, abnormal ECG indicators, heart rhythm, heart rate and pulse disorders; rarely-pericardial effusion; very rarely-abnormal echocardiogram indicators.

Blood and lymphatic system:  often-anemia, leukopenia, thrombocytopenia, leukocytosis; infrequently-coagulopathy, deviation in coagulogram parameters, pancytopenia, neutropenia; rarely-thrombotic thrombocytopenic purpura, hypoprothrombinemia.

The nervous system:  very often-tremor, headache; often-epileptoid seizures, impaired consciousness, paresthesia and dysesthesia, peripheral neuropathies, dizziness, writing disorders, nervous system disorders; infrequently-coma, central nervous system hemorrhages and cerebral circulation disorders, paralysis and paresis, encephalopathy, speech and articulation disorders, amnesia; rarely — increased muscle tone; very rarely — myasthenia gravis.

Organs of vision:  often — blurred vision, photophobia, eye diseases; infrequently-cataracts; rarely-blindness.

Organs of hearing and balance:  often-tinnitus; infrequently-hearing loss; rarely-sensorineural deafness; very rarely-hearing disorders.

Respiratory system and mediastinum:  often — shortness of breath, pulmonary parenchymal disorders, pleural effusion, pharyngitis, cough, nasal congestion, rhinitis; infrequently — respiratory failure, respiratory tract disorders, asthma; rarely — acute respiratory distress syndrome.

Gastrointestinal disorders:  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, feeling of bloating and bursting in the abdomen, loose stools, infrequently-paralytic intestinal obstruction (paralytic ileus), peritonitis, acute and chronic pancreatitis, increased blood amylase, gastroesophageal reflux disease, violation of gastric evacuation function, rarely-subileus, pancreatic pseudocysts.

Kidneys and urinary tract:  very often-impaired renal function; often-renal failure, including acute, oliguria, acute tubular necrosis, toxic nephropathy, urinary syndrome; infrequently-anuria, hemolytic uremic syndrome; very rarely-nephropathy, hemorrhagic cystitis.

Skin and subcutaneous tissue:  often — pruritus, rash, alopecia, acne, hyperhidrosis; infrequently-dermatitis, photosensitization; rarely-toxic epidermal necrolysis (Lyell’s syndrome); very rarely-Stevens-Johnson syndrome.

Musculoskeletal system and connective tissue:  often-arthralgia, muscle cramps, pain in the extremities, back pain; infrequently-joint disorders.

Endocrine system:  rarely-hirsutism.

Metabolism and nutrition: very often — hyperglycemia, diabetes mellitus, hyperkalemia; often — hypomagnesemia, hypophosphatemia, hypokalemia, hypocalcemia, hyponatremia, hypervolemia, hyperuricemia, decreased appetite, anorexia, metabolic acidosis, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, electrolyte disorders; infrequently — dehydration, hypoproteinemia, hyperphosphatemia, hypoglycemia.

The immune system: tacrolimus therapy, as with other immunosuppressants, increases the risk of local and generalized infectious diseases (viral, bacterial, fungal, protozoal). The course of previously diagnosed infectious diseases may worsen. Cases of VC-associated nephropathy and progressive JC-associated multifocal leukoencephalopathy (PML) have been reported with immunosuppressive therapy, including Advagraf therapy.

Injuries, poisoning, complications of procedures: often — primary graft dysfunction.

Benign, malignant, and unidentified neoplasms. Patients receiving immunosuppressive therapy have a higher risk of developing malignant tumors. When using tacrolimus, the occurrence of both benign and malignant neoplasms, including Epstein-Barr virus (EBV) — associated lymphoproliferative diseases and skin cancer, was noted.

Vascular system: very often-arterial hypertension; often-bleeding, thromboembolic and ischemic complications, peripheral circulatory disorders, hypotension; infrequently-heart attack, deep vein thrombosis of the extremities, shock.

Common disorders and complications: often — asthenia, fever, edema, pain and discomfort, increased ALP levels in the blood, weight gain, body temperature perception disorders; infrequently — multiple organ failure, flu — like syndrome, impaired perception of ambient temperature, chest tightness, anxiety, poor health, increased lactate dehydrogenase levels in the blood, weight loss; rarely — thirst, loss of balance (falling), feeling of stiffness in the chest, difficulty moving; very rarely-increase in fat mass fabrics.

Immune system (allergic reactions). Allergic and anaphylactic reactions were observed in patients taking tacrolimus.

Liver and biliary tract: often-increased liver enzymes, liver function disorders, cholestasis and jaundice, liver cell damage and hepatitis, cholangitis; rarely-hepatic artery thrombosis, obliterating endophlebitis of the hepatic veins; very rarely-liver failure, bile duct stenosis.

Reproductive system and mammary glands: infrequently-dysmenorrhea and uterine bleeding.

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

The psychic sphere: very often-insomnia; often-anxiety, confusion and disorientation, depression, depressed mood, emotional disorders, nightmares, hallucinations, mental disorders; infrequently-psychotic disorders.

Interaction

Metabolic interactions

After oral use, tacrolimus is metabolized in the intestinal cytochrome CYP3A4 system. Concomitant use of drugs or medicinal herbs with an established inhibitory or inducing effect on CYP3A4 may increase or decrease the concentration of tacrolimus in the blood, respectively. Therefore, to maintain adequate and consistent exposure to tacrolimus, it is recommended to monitor the concentration of tacrolimus in the blood and, if necessary, adjust the dose of Advagraf.

Metabolic inhibitors. Based on clinical experience, it was found that the following drugs can significantly increase the concentration of tacrolimus in the blood: antifungal agents (ketoconazole, fluconazole, itraconazole, voriconazole), macrolide antibiotics (erythromycin), HIV protease inhibitors (ritonavir). When prescribing these drugs with tacrolimus, it may be necessary to reduce the dose of Advagraf. Pharmacokinetic studies have shown that an increase in the level of tacrolimus in the blood is primarily a consequence of an increase in the oral bioavailability of the drug caused by inhibition of the intestinal metabolism of tacrolimus. Suppression of hepatic metabolism of tacrolimus plays a secondary role.

Less pronounced drug interactions were observed when tacrolimus was co-administered with clotrimazole, clarithromycin, josamycin, nifedipine, nicardipine, diltiazem, verapamil, danazol, ethinyl estradiol, omeprazole, and nefazodone.

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

It is also recommended to avoid consuming grapefruit juice due to the possibility of increasing the level of tacrolimus in the blood. Lansoprazole and cyclosporine can potentially inhibit the CYP3A4-mediated metabolism of tacrolimus and increase its concentration in the blood.

Inducers of metabolism. Based on clinical experience, it was found that the concentration of tacrolimus in the blood can significantly reduce rifampicin, phenytoin and St. John’s wort (Hypericum perforatum). When prescribing these drugs with tacrolimus, it may be necessary to increase the dose of Advagraf.

Clinically significant interactions were observed with phenobarbital.

Corticosteroids in maintenance doses usually reduce the concentration of tacrolimus in the blood. High doses of prednisone or methylprednisolone used to treat acute rejection may increase or decrease tacrolimus levels in the blood.

Carbamazepine, metamizole and isoniazid may reduce the concentration of tacrolimus in the blood.

The effect of tacrolimus on the metabolism of other drugs. Tacrolimus inhibits CYP3A4 and, when taken concomitantly, may affect drugs that are metabolized in the CYP3A4 system. The half-life of cyclosporine increases when co-administered with tacrolimus. Synergistic / additive nephrotoxic effects may also occur. For these reasons, concomitant use of cyclosporine and tacrolimus is not recommended, and caution should be exercised when prescribing tacrolimus to patients who have previously taken cyclosporine.

Tacrolimus increases the level of phenytoin in the blood.

Since tacrolimus can reduce the clearance of hormonal contraceptives, it is important to use caution when choosing contraceptives.

Data on the interaction of tacrolimus with statins are limited. Clinical observations suggest that the pharmacokinetics of statins do not change when taken concomitantly with tacrolimus.

Experimental animal studies have shown that tacrolimus has the potential to reduce clearance and increase the half-life of phenobarbital and antipyrine.

Other potential interactions that increase systemic exposure to tacrolimus: prokinetic agents (metoclopramide, cisapride), cimetidine, magnesium and aluminum hydroxide.

Other potentially adverse drug interactions. Concomitant use of tacrolimus with drugs that have nephrotoxicity or neurotoxicity (for example, aminoglycosides, gyrase inhibitors, vancomycin, co-trimoxazole, NSAIDs, ganciclovir, acyclovir) may increase these effects.

Concomitant use of tacrolimus with amphotericin B and ibuprofen resulted in increased nephrotoxicity.

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

Immunosuppressants can alter the body’s response to vaccination: vaccination during tacrolimus treatment may be less effective. Live attenuated vaccines should be avoided.

Binding to proteins. Tacrolimus actively binds to plasma proteins. Consideration should be given to the possible competitive interaction of tacrolimus with drugs that have a high affinity for plasma proteins (NSAIDs, oral anticoagulants, oral antidiabetic agents).

Incompatibility. Tacrolimus is incompatible with polyvinyl chloride (PVC). Test tubes, syringes and other equipment used in the preparation of Advagraf capsule suspension must not contain PVC.

How to take it, course of use and dosage

Advagraf® is an oral once-daily form of tacrolimus. Advagraf therapy requires careful monitoring by appropriately qualified personnel who have the necessary equipment at their disposal. This drug can only be prescribed by doctors who have experience in immunosuppressive therapy in patients with transplanted organs.

Uncontrolled transfer of patients from one tacrolimus drug to another (including switching from regular capsules to long-acting capsules) is unsafe. This may lead to graft rejection or an increased incidence of side effects, including hypo-or hyperimmunosuppression, due to clinically significant differences in tacrolimus exposure. The patient should take one of the dosage forms of tacrolimus in compliance with the recommended dosage regimen. Changing the dosage form or dosage regimen should only be carried out under the supervision of a specialist in the field of transplantology.After 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 listed 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 immunosuppressive therapy regimen. The choice of dose of Advagraf® should be based primarily on the clinical assessment of the risk of rejection and individual tolerability of the drug, as well as on data from monitoring the concentration of tacrolimus in the blood (see the section “Recommendations for monitoring the therapeutic concentration of tacrolimus in the blood”below).

If clinical signs of rejection appear, consideration should be given to the need to adjust the immunosuppressive therapy regimen.

In patients after de novo kidney and liver transplantation, the PFC of 0-24 tacrolimus on day 1 of Advagraf® use was 30% and 50% lower, respectively, compared to the equivalent doses of Prograf. By day 4, the systemic exposure of tacrolimus, estimated by Co, when using Prograf and Advagraf® preparations in patients after liver and kidney transplantation was the same. In order to ensure adequate exposure to tacrolimus during treatment with Advagraf® during the first two weeks after transplantation, regular and careful monitoring of the minimum (Co) concentration of tacrolimus in the blood is recommended. Since tacrolimus is a low-clearance substance, it may take several days to reach steady-state concentrations after adjusting the dose of Advagraf®. For patients who cannot take the drug orally immediately after transplantation, tacrolimus can be administered intravenously (Prograf® 5 mg / ml, concentrate for preparing an intravenous solution) at a dose of approximately one-fifth of the recommended oral dose for this indication.

Method of application

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

Duration of taking the drug

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

Dosage recommendations

Prevention of rejection after kidney transplantation

Oral therapy with Advagraf® should begin with a daily dose of 0.20-0.30 mg / kg, once a day in the morning. The drug should be started within 24 hours after the transplant. Over time after transplantation, the dose of Advagraf® is usually reduced. In some cases, it is possible to cancel concomitant immunosuppressants, that is, switch to monotherapy with Advagraf®. Improvement in the patient’s condition may alter the pharmacokinetics of tacrolimus and require additional dose adjustment of Advagraf®.

Prevention of rejection after liver transplantation

Oral therapy with Advagraf® should begin with a daily dose of 0.10-0.20 mg / ct, once a day in the morning. The drug should be started 12-18 hours after transplantation. Over time after transplantation, the dose of Advagraf® is usually reduced. In some cases, it is possible to cancel concomitant immunosuppressants, that is, switch to ion therapy with Advagraf®. Improvement in the patient’s condition may alter the pharmacokinetics of tacrolimus and require additional dose adjustment of Advagraf®.

Conversion rate from Prograph to Advagraphk

If post-allograft patients taking Prograf twice a day need to be transferred to Advagraf once a day, the ratio of daily doses during the transfer period should be 1: 1 (mg:mg). Advagraf® is recommended to be taken in the morning.

In stable patients transferred from Prograf (twice daily intake) to Advagraf® (single daily intake), with a total daily dose of 1:1 (mg:mg), the systemic exposure of tacrolimus (area under the pharmacokinetic curve of PFC 0.24) when taking Advagraf® was approximately 10% lower compared to Prograf. The relationship between minimum tacrolimus concentrations (C24) and systemic exposure to Advagraf® was the same as with Prograf. When switching from Prograph to Advagraf®, minimum tacrolimus concentrations should be measured both before conversion from one drug to another, and over the next two weeks. At the same time, the dose of Advagraf® should be adjusted in order to achieve a systemic exposure of tacrolimus similar to Prograf.

Conversion rate from cyclosporine to Advagrafk

Caution should be exercised when switching from cyclosporine to Advagraf. Concomitant use of cyclosporine and tacrolimus is not recommended. Treatment with Advagraf® is recommended to begin after determining the concentrations of cyclosporine in the blood and evaluating the patient’s clinical condition. Conversion should be delayed if there are elevated blood concentrations of cyclosporine. In practice, tacrolimus therapy begins 12-24 hours after cyclosporine discontinuation. After the transition, it is recommended to monitor the concentration of cyclosporine in the blood, since cyclosporine clearance may slow down.

Treatment of graft rejection

In order to stop graft rejection, the following approaches are recommended: increasing the dose of tacrolimus, increasing therapy with glucocorticosteroids, and short courses of therapy with mono- / polyclonal antibodies. If signs of tacrolimus toxicity occur (for example, severe adverse reactions), it may be necessary to reduce the dose of Advagraf®.

Kidney or liver transplantation

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

Heart Transplantation

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

Transplanting other organones

There is no clinical experience of using Advagraf® for the treatment of patients after lung, pancreatic, and intestinal transplants. However, gacrolimus (Prograf) is used in patients with lung transplants at an initial oral dose of 0.10-0.15 mg / kg / day, after pancreatic transplantation at an initial oral dose of 0.2 mg/kg / day, after intestinal transplantation at an initial oral dose of 0.3 mg / kg / day.

Recommendations for monitoring the therapeutic concentration of tacrolimus in the blood

The choice of doses should be based on a clinical assessment of the individual risk of rejection and tolerability of the drug, as well as on data from monitoring the concentration 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 the results of monitoring published in the literature with the results of monitoring in a separate clinic should be carried out taking into account the method used to determine the concentration of tacrolimus in the blood. In modern clinical practice, tacrolimus concentrations in the blood are mainly controlled by immunoassay methods.

Correlation between minimum (C (), C24) concentrations and systemic exposure (AUC 0.24) of tacrolimus in the blood when using both drugs. Advagraf® and Prograf are the same.

In the post-transplant period, careful monitoring of the minimum (Co, C24) concentrations of tacrolimus in the blood is necessary. The minimum blood concentrations of Advagraf® should be determined approximately 24 hours after taking the drug, before taking the next dose. In the first two weeks after transplantation, it is recommended to monitor the minimum concentration more frequently, then periodically monitor it during maintenance therapy. The therapeutic concentration of tacrolimus in the blood should be monitored with special care after switching from Prograph to Advagraf®, when adjusting drug doses, when making changes to the immunosuppressive therapy regimen, or when using drugs that may cause a change in tacrolimus concentrations in the blood (see the sections “Conversion (transition) from cyclosporine to Advagraf®”, “Conversion (transition) from Prograph to Advagraf®” and “Interaction with other drugs”). The frequency of monitoring the drug concentration in the blood is determined by clinical necessity. Since Advagraf® is a low-clearance drug, it may take several days to reach steady-state blood concentrations of tacrolimus after adjusting the dose of Advagraf®.

According to clinical studies, in most cases, treatment is successful at therapeutic concentrations of tacrolimus in the blood no higher than 20 ng / ml. When interpreting data on the therapeutic concentration of tacrolimus in the blood, it is necessary to take into account the patient’s clinical condition.

According to available data, in the initial post-transplant period in patients after liver transplantation, 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 liver, kidney or heart transplantation, blood concentrations of the drug are usually in the range of 5-15 ng / ml.

Dose adjustment for certain categories of patients Patients with hepatic dysfunction

In patients with severe hepatic dysfunction, it may be necessary to reduce the dose of Advagraf®in order to maintain the minimum (Co) concentrations 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 for dose adjustment. However, due to the nephrotoxic potential of tacrolimus, careful monitoring of renal function is recommended (including determination of serum creatinine concentration, calculation of creatinine clearance, and control of the amount of urine excreted).

Race

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

Gender

There is no evidence that men and women require different doses of the drug to achieve equal minimum (Co) concentrations of tacrolimus in the blood.

Elderly patients

There is no evidence that elderly patients require special doses of Advagraf®.

Children

Dosage recommendations for children under 18 years of age are not available due to limited clinical experience.

Overdose

Symptoms: information about overdose is limited. Several episodes of accidental overdose have been reported in patients taking tacrolimus. Symptoms included tremors, headache, nausea, vomiting, infections, hives, lethargy, elevated blood urea nitrogen, serum creatinine, and alanine aminotransferase.

Treatment: Currently, there are no antidotes to tacrolimus. In case of overdose, standard measures should be taken and symptomatic treatment should be carried out.

Given the high molecular weight of tacrolimus, poor water solubility, and pronounced binding to red blood cells and plasma proteins, dialysis is ineffective. In some patients with very high blood concentrations of tacrolimus, hemofiltration or diafiltration was effective. In cases of oral overdose, gastric lavage and/or the use of adsorbents (such as activated charcoal) may be effective if these measures are taken shortly after taking the drug.

Special instructions

Experience in the treatment of non-white patients, as well as patients with high immunological risk (i. e., with repeated transplantation, high titer of panel reactive antibodies — PRA) is limited. There are no clinical data on the use of Advagraf in acute rejection that is refractory to therapy with other immunosuppressants in adult patients.

Currently, there are no clinical data on the use of Advagraf for the prevention of graft rejection during heart 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), liver and kidney function, hematological parameters, coagulogram, and proteinemia level. In the presence of clinically significant changes, correction of immunosuppressive therapy is necessary.

When using Advagraf, you should avoid prescribing herbal preparations containing St. John’s wort (Hypericum perforatum), as well as other herbal remedies that may 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; if diarrhea occurs, careful monitoring of tacrolimus concentrations in the blood is necessary.

Concomitant use of cyclosporine and tacrolimus should be avoided, and caution should be exercised when treating patients who have previously received cyclosporine with tacrolimus (see section ” Conversion from cyclosporine to Advagraf®”).

Cases of ventricular hypertrophy or septal hypertrophy reported as cardiomyopathy are rare, but have been observed in patients taking Prograf and are therefore possible with Advagraf treatment. In most cases, myocardial hypertrophy was reversible and was observed at concentrations (C0) of tacrolimus in the blood exceeding the recommended values. Other factors that increase the risk of this adverse event include: the presence of previous heart disease, corticosteroid use, hypertension, renal and hepatic dysfunction, infections, hypervolemia, and edema. Patients at high risk and receiving intensive immunosuppressive therapy should be monitored by echocardiography and ECG before and after transplantation (after 3 and 9-12 months). If abnormalities are detected, consideration should be given to reducing the dose of Advagraf or replacing the drug with another immunosuppressant.

Tacrolimus may cause prolongation of the QT interval, while no “pirouette” – type cardiac arrhythmias (bidirectional fusiform ventricular tachycardia) were observed. Special care should be taken when treating patients who have been diagnosed with congenital long QT syndrome or are suspected of having such a condition.

Patients treated with tacrolimus may develop post-transplant lymphoproliferative diseases (PTLDS) associated with the Epstein-Barr virus. Concomitant use of the drug with anti-lymphocytic antibodies increases the risk of PTLD. There is also evidence of an increased risk of PTLD in patients with a detected Epstein-Barr virus capsid antigen. Therefore, before prescribing Advagraf in this group of patients, a serological study should be performed for the presence of Epstein-Barr virus capsid antigen. During treatment, it is recommended to conduct careful monitoring for Epstein-Barr virus using polymerase chain reaction (PCR). Positive PCR for Epstein-Barr virus can persist for months and is not in itself evidence of PTHD or lymphoma.

Patients receiving immunosuppressive therapy, including Advagraf®, have an increased risk of opportunistic infections (caused by bacteria, fungi, viruses, protozoa). These infections include VC-associated nephropathy and JC-associated progressive multifocal leukoencephalopathy (PML). Such infections are often associated with profound suppression of the immune system and can lead to severe or fatal outcomes, which should be taken into account when making 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 malignancies. It is recommended to limit sun exposure and UV exposure, wear appropriate clothing, and use sunscreens with a high protection factor.

The risk of developing secondary cancer is unknown.

Reversible posterior encephalopathy syndrome has been reported with tacrolimus therapy. If a patient taking tacrolimus develops symptoms that are characteristic of reversible posterior encephalopathy syndrome — headache, mental disorders, seizures, and visual disturbances — an MRI scan should be performed. If the diagnosis is confirmed, it is necessary to exercise adequate control over blood pressure and seizures, and immediately stop the systemic use of tacrolimus. If these measures are taken, this condition is completely reversible in most patients.

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

Influence on the ability to drive vehicles and work with mechanisms

Tacrolimus can cause visual and neurological disorders, especially when combined with alcohol.

Form of production

Long-acting capsules.

Storage conditions

At a temperature not exceeding 25 °C, in the original packaging

Shelf life

3 years

Active ingredient

Tacrolimus

Conditions of release from pharmacies

By prescription

Dosage form

long-acting capsules

Purpose

Adults on doctor’s prescription