Tacrolimus, 1 mg capsules 50 pcs

Prevention of liver, kidney, or heart allograft rejection.

Treatment of allograft rejection resistant to other immunosuppressive regimens.

Indications

Prevention of liver, kidney, or heart allograft rejection.

Treatment of allograft rejection resistant to other immunosuppressive regimens.

Active ingredient

Composition

11 mg capsule contains:

Active ingredient:

Tacrolimus monohydrate – 1.02 mg, in tacrolimus equivalent – 1.00 mg.

Excipients:

Lactose – 133.84 mg;

Vinous acid – 0.14 mg;

Hyprolose – 0.10 mg;

p> Croscarmellose sodium – 2.80 mg;

Silicon dioxide colloid – 0.70 mg;

Magnesium stearate – 1.40 mg.

Capsule body composition:

Titanium dioxide – 2%;

Gelatin – up to 100%.

Capsule cap composition:

Titanium dioxide – 2 %;

Gelatin – up to 100 %.

How to take, the dosage

Tacrolimus therapy requires close monitoring by appropriately trained and equipped personnel. Only physicians experienced in immunosuppressive therapy in organ transplant patients should prescribe tacrolimus or make changes to immunosuppressive therapy.

The uncontrolled transfer of patients from one tacrolimus medication to another (including switching from conventional capsules to prolonged capsules) is unsafe. This can 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 tacrolimus dosage forms and follow the recommended dosing regimen. A change in dosage form or dosing regimen should only be made under the supervision of a transplant specialist. After transfer, tacrolimus blood concentrations should be monitored closely and the dose of the drug should be adjusted to maintain systemic tacrolimus exposure at an adequate level.

If tacrolimus capsules are missed, the next dose should be taken in time. A double dose of the drug should not be taken.

General points

The initial doses below should be considered as recommendations only. In the initial postoperative period, tacrolimus is usually used in combination with other immunosuppressants. The dose may vary depending on the immunosuppressive therapy regimen. The choice of tacrolimus dose should be based primarily on a clinical evaluation of the risk of rejection and individual tolerance to the drug, as well as on data on monitoring of tacrolimus blood concentrations (see section “Recommendations for monitoring therapeutic tacrolimus blood concentrations” below).

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

Tacrolimus can be used both orally and intravenously. In most cases, tacrolimus in capsule form is given orally; if needed, the contents of the capsules can be mixed with water and injected through a nasogastric tube.

Method of administration and dosage

The daily dose of Tacrolimus capsule form is divided into 2 doses (morning and evening) in equal doses. The capsules should be taken immediately after removing them from the blister.

The capsules are taken with liquids, preferably water. For maximum absorption, it is recommended to take the capsules on an empty stomach 1 hour before or 2-3 hours after a meal.

The duration of therapy

In order to prevent transplant rejection, immunosuppression must be maintained at all times, so there is no limit to the duration of therapy.

Liver transplantation

Prevention of allograft rejection – adults

p> Oral therapy with Tacrolimus capsules should be started with a dose
0.10-0.20 mg/kg/day, divided into two doses (e.g., in the morning and evening). If the patient’s condition allows oral administration, Tacrolimus capsules should be started approximately 12 hours after completion of surgery.

If the patient’s condition does not permit oral medication, intravenous therapy should be started at a dose of 0.01-0.05 mg/kg/day, administered as a continuous 24-hour infusion of tacrolimus.

Prevention of allograft rejection – children

The starting dose of 0.30 mg/kg/day of Tacrolimus should be divided into two doses (e.g., morning and evening).

If the patient’s clinical condition does not allow for oral medication, start intravenous therapy with Tacrolimus at 0.05 mg/kg/day as a continuous 24-hour infusion.

Supportive therapy – adults and children

In the post-transplant period, doses of Tacrolimus are usually reduced. In some cases, concomitant immunosuppressive therapy may be discontinued, leaving tacrolimus as monotherapy. Improvement of the patient after transplantation may change the pharmacokinetics of tacrolimus, and a dose adjustment will be necessary.

Treatment of rejection – adults and children

Higher doses of tacrolimus capsules combined with additional corticosteroid therapy and short courses of mono/polyclonal antibody administration are needed to treat episodes of rejection. If signs of toxicity are noted, reduction of the drug dose may be required.

If patients are transferred to tacrolimus capsule therapy, the same initial doses are recommended as for initial immunosuppression. Information about switching patients from cyclosporine to tacrolimus therapy is provided at the end of the section “Dose Adjustment in Special Populations of Patients”.

TKidney transplantation

Prevention of allograft rejection – adults.

The oral therapy with tacrolimus should be started with a dose of 0.20-0.30 mg/kg/day divided into two doses (e.g., morning and evening). Therapy with the drug should be started within 24 hours after completion of surgery.

If the patient’s condition does not allow for oral therapy, then intravenous therapy should be started at a dose of 0.05-0.10 mg/kg/day as a continuous 24-hour infusion.

Prevention of allograft rejection – children

The initial dose of 0.30 mg/kg/day of tacrolimus capsules should be divided into two doses (e.g., morning and evening).

If the patient’s clinical condition does not allow for oral therapy, start intravenous therapy with a dose of 0.075-0.100 mg/kg/day as an intravenous infusion over 24 hours.

Supportive therapy – adults and children

The doses of tacrolimus are usually reduced during supportive therapy. In some cases it is possible to withdraw concomitant immunosuppressants, leaving tacrolimus as the base component of dual therapy. Improvement of the patient after transplantation may change the pharmacokinetics of tacrolimus, and a dose adjustment will be necessary.

Treatment of rejection reactions – adults and children

Higher doses of tacrolimus combined with additional corticosteroid therapy and short courses of mono/polyclonal antibodies are needed to treat episodes of rejection. If signs of toxicity are noted, reduction of the drug dose may be required.

If patients are transferred to tacrolimus capsule therapy, the same initial doses are recommended as for initial immunosuppression. Information about switching patients from cyclosporine to tacrolimus therapy is provided at the end of the section “Dose Adjustment in Special Populations of Patients”.

Heart transplantation

Prevention of allograft rejection – adults

. Tacrolimus can be used in combination with antibody induction therapy (which allows delayed initiation of tacrolimus) or without antibody administration in clinically stable patients. Following antibody induction, oral therapy with tacrolimus capsules should be started at a dose of 0.075 mg/kg/day divided into two doses (e.g., morning and evening) for 5 days after surgery as soon as the patient’s clinical condition stabilizes. If the patient’s condition does not permit oral administration, intravenous therapy should be initiated with a dose of 0.01-0.02 mg/kg/day as a continuous 24-hour infusion. There is an alternative approach in which oral tacrolimus administration is started within 12 hours after transplantation. This approach is intended for patients without signs of internal organ dysfunction (e.g., kidneys). In this case, tacrolimus at an initial dose of 2-4 mg/day is combined with mycophenolate mofetil and corticosteroids or sirolimus and corticosteroids.

Prevention of allograft rejection – children

After cardiac transplantation in children, primary immunosuppression with tacrolimus may be performed either in combination with antibody induction or alone. When antibody induction is not performed and tacrolimus is administered intravenously, the recommended initial dose is 0.03-0.05 mg/kg/day as a continuous
24-hour infusion until tacrolimus concentration in whole blood
15-25 ng/ml is achieved. At the earliest clinical opportunity, the patient should be switched to oral administration. The initial oral dose should be
0.30 mg/kg/day and administered 8-12 hours after stopping the intravenous infusion.

After antibody induction, oral tacrolimus should be started at a dose
0.10-0.30 mg/kg/day divided into two doses (e.g., morning and evening).

Supportive therapy – adults and children

Doses of tacrolimus are usually reduced during supportive therapy. Improvement of the patient after transplantation may change the pharmacokinetics of tacrolimus, and a dose adjustment will be necessary.

Treatment of rejection reactions – adults and children

The treatment of rejection episodes requires higher doses of tacrolimus in combination with additional corticosteroid therapy and short courses of mono/polyclonal antibody administration.

The initial daily dose (0.15 mg/kg/day in adults; 0.2-0.3 mg/kg/day in children) should be divided into two doses (e.g., in the morning and in the evening) when patients are switched to tacrolimus capsule therapy.

Information on switching patients from cyclosporine therapy to tacrolimus is provided at the end of the section “Dose Adjustment of the Drug in Special Populations of Patients”.

Recommended doses for the treatment of rejection after allotransplantation of other organs

The recommendations for tacrolimus dosing for patients after lung, pancreatic and small intestine allotransplantation are based on data from selected prospective clinical trials. After lung transplantation, tacrolimus is used at a starting dose of 0.10-0.15 mg/kg/day, pancreatic allotransplantation at a starting dose of 0.2 mg/kg/day. In patients after small intestine allotransplantation the initial dose of the drug is 0.3 mg/kg/day.

Correction of the drug dose in special patient populations

Patients with hepatic impairment

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

Patients with renal impairment

Because the pharmacokinetics of tacrolimus do not change with renal function, no dose adjustment is required. However, due to the nephrotoxic effect of tacrolimus, careful monitoring of renal function (including serum creatinine concentration, creatinine clearance and diuresis level) is recommended.

Children

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

Elderly patients

There is currently no evidence that the drug dose needs to be adjusted for elderly patients.

Transfer from cyclosporine therapy

The concomitant use of cyclosporine and tacrolimus medications may increase the elimination half-life of cyclosporine and exacerbate toxic effects. Therefore, caution should be exercised when transferring patients from cyclosporine to tacrolimus therapy. Treatment with tacrolimus capsules should be started after evaluation of cyclosporine blood concentrations and clinical condition of the patient. Transition to tacrolimus should be delayed in the presence of elevated concentrations of cyclosporine in the patient’s blood. In practice, tacrolimus is administered 12-24 hours after cyclosporine withdrawal. After transfer, the patient’s cyclosporine blood concentrations should continue to be monitored due to the possibility of impaired cyclosporine clearance.

Recommendations for monitoring therapeutic tacrolimus blood concentrations

The choice of tacrolimus capsule dose should be based on clinical rejection assessment data and tolerability of the drug in each individual patient. In order to optimize dosing, determination of tacrolimus concentrations in whole blood by immune methods, including a semi-automated microparticle immunoassay (MIFA), is used. Comparisons of tacrolimus blood concentrations published in the literature with individual clinical values should be made with caution and based on knowledge and understanding of the assessment method used.

In the postoperative period, it is important to monitor minimum tacrolimus concentrations in whole blood. When tacrolimus capsules are administered orally, blood samples should be obtained 12 hours after administration of the medication immediately prior to the next dose to determine minimum tacrolimus concentrations in the blood. The frequency of determining tacrolimus blood concentrations should depend on clinical needs. Because tacrolimus is a low clearance drug, it may take several days for tacrolimus to reach equilibrium minimum blood concentrations after adjusting the dose. Minimum tacrolimus blood concentrations should be monitored approximately twice weekly during the early post-transplant period and periodically thereafter during maintenance therapy. Minimum tacrolimus blood concentrations should also be monitored after changes in tacrolimus capsule dose, immunosuppression regimen or after co-administration with drugs that affect tacrolimus concentrations in whole blood.

The results of clinical studies suggest that treatment with tacrolimus capsules is most successful when minimum tacrolimus blood concentrations do not exceed 20 ng/ml. When interpreting data on whole blood tacrolimus concentrations, it is important to assess the patient’s clinical condition.

In clinical practice, in the early post-transplant period, minimum whole blood tacrolimus concentrations typically range from 5-20 ng/ml after liver transplantation and 10-20 ng/ml after kidney and heart transplantation. Thereafter, during maintenance therapy after liver, kidney and heart transplantation, tacrolimus blood concentrations range from 5 to 15 ng/ml.

Interaction

Metabolic interactions

Tacrolimus in the systemic blood stream is metabolized in the liver by the CYP3A4 isoenzyme of cytochrome P450 system. When administered orally, tacrolimus is also metabolized by the intestinal wall CYP3A4 isoenzyme of cytochrome P450 system. Concomitant administration of drugs or medicinal plants with an established inhibitory or inducing effect on the CYP3A4 isoenzyme may respectively increase or decrease tacrolimus blood concentrations. To maintain adequate and constant tacrolimus concentrations when concomitantly used with drugs that may alter the activity of CYP3A4 isoenzyme or have other effects on tacrolimus pharmacokinetics, it is recommended to monitor the tacrolimus blood concentration and, if necessary, adjust the dose or discontinue the drug. The QT interval (with electrocardiography), renal function, and possible side effects should also be monitored.

Metabolic inhibitors

Based on clinical experience, it has been found that the following drugs can significantly increase tacrolimus blood concentrations: Antifungal agents (ketoconazole, fluconazole, itraconazole, voriconazole), macrolide antibiotics (erythromycin), HIV protease inhibitors (ritonavir, nelfinavir, saquinavir) or hepatitis C virus protease inhibitors (eg, telaprevir, boceprevir). When concomitant use of these drugs with tacrolimus, reduction of doses of tacrolimus may be required in almost all patients. Less pronounced drug interactions have been observed with concomitant use of tacrolimus with clotrimazole, clarithromycin, josamycin, nifedipine, nicardipine, diltiazem, verapamil, amiodarone, danazol, ethinylestradiol, omeprazole and nefazodone.

The following substances have been shown in in vitro studies to be potential inhibitors of tacrolimus metabolism: bromocriptine, cortisone, dapsone, ergotamine, gestodine, lidocaine, mephenytoin, miconazole, midazolam, nilvadipine, norethisterone, quinidine, tamoxifen, (triacetyl)oleandomycin.

Grapefruit juice should be avoided due to the possibility of increased tacrolimus blood concentrations. Lansoprazole and cyclosporine may potentially inhibit SURSA4-mediated metabolism of tacrolimus and increase its blood concentration.

Metabolism inducers

Based on clinical experience, it has been found that the following drugs can significantly reduce tacrolimus blood concentrations: rifampicin, phenytoin, St. John’s wort (Hypericum perforatum). Their concomitant use may require increased doses of tacrolimus in almost all patients. Clinically significant interactions have been observed with phenobarbital. Glucocorticosteroids in maintenance doses usually decrease the blood concentration of tacrolimus. High doses of prednisolone or methylprednisolone used to treat acute rejection can increase or decrease the blood concentration of tacrolimus.

Carbamazepine, methamizole and isoniazid can decrease the blood concentration of tacrolimus.

The effect of tacrolimus on the metabolism of other drugs

Tacrolimus inhibits the CYP3A4 isoenzyme and may affect drugs metabolized by CYP3A4 when taken simultaneously. The elimination half-life of cyclosporine is prolonged when used concomitantly with tacrolimus. Synergistic/additive nephrotoxic effects may also be observed. For these reasons, concomitant administration 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 blood concentration of phenytoin.

Because tacrolimus may decrease the clearance of hormonal contraceptives, it is important to use caution when choosing contraception.

The data on interactions of tacrolimus with statins are limited. Clinical observations suggest that the pharmacokinetics of statins are not altered by concomitant administration with tacrolimus.

Animal experimental studies have shown that tacrolimus has the potential to decrease clearance and increase the half-life of pentobarbital and phenazole.

Other potential interactions that increase the systemic exposure of tacrolimus

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

Other potentially adverse drug interactions

Concomitant use of tacrolimus with drugs with nephrotoxicity or neurotoxicity (e.g., aminoglycosides, gyrase inhibitors, vancomycin, cotrimoxazole, nonsteroidal anti-inflammatory drugs, ganciclovir, acyclovir) may contribute to these effects.

Tacrolimus combined with amphotericin B and ibuprofen resulted in increased nephrotoxicity.

Because tacrolimus may contribute to or exacerbate hyperkalemia, high doses of potassium or potassium-saving diuretics (amiloride, triamterene, spironolactone) should be avoided.

The immunosuppressants may change the body’s response to vaccination: vaccination during treatment with tacrolimus may be less effective. Live, attenuated vaccines should be avoided.

Protein binding

Tacrolimus actively binds to plasma proteins. Possible competitive interaction of tacrolimus with drugs with high affinity to plasma proteins (non-steroidal anti-inflammatory drugs, anticoagulants for oral use, hypoglycemic agents for oral use) should be considered.

Incompatibilities

Tacrolimus is incompatible with polyvinyl chloride (PVC). Test tubes, syringes, and other equipment used when preparing a suspension of Tacrolimus capsules must not contain PVC.

Special Instructions

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

In practice, errors in the use of tacrolimus have been observed, including unreasonable, unintentional or uncontrolled transfer of patients from one form of tacrolimus (standard or prolonged) to another. This has resulted in serious adverse events, including graft rejection or other side effects, which may have resulted from hypo- or hyperimmunosuppression resulting from clinically significant differences in the systemic effects of tacrolimus. The patient should be managed on one of the dosage forms of tacrolimus with an appropriate dosing regimen; changes in the dosage form or regimen should only be made under the supervision of a transplant specialist.

. When tacrolimus and strong CYP3A4 isoenzyme inhibitors (e.g., telaprevir, boceprevir, ritonavir, ketoconazole, voriconazole, itraconazole, telithromycin or clarithromycin) or CYP3A4 isoenzyme inducers (e.g., rifampicin, rifabutin) are used simultaneously, the blood tacrolimus concentration should be monitored for timely dose adjustment.

When using tacrolimus, prescribing herbal remedies containing Hypericum perforatum and other herbal remedies that may decrease (change) tacrolimus blood concentrations and adversely affect the therapeutic effect of the drug should be avoided.

In diarrhea, tacrolimus blood concentrations may change significantly; close monitoring of tacrolimus blood concentrations is necessary if diarrhea occurs.

The concomitant use of cyclosporine and tacrolimus should be avoided, and caution should be exercised when treating patients who have previously received cyclosporine with tacrolimus.

Cases of ventricular hypertrophy or cardiac septal hypertrophy reported as cardiomyopathy are rare but have been observed in patients treated with tacrolimus. In most cases, myocardial hypertrophy was reversible and was observed at blood concentrations (Co) of tacrolimus well in excess of the maximum recommended. Other factors that increase the risk of this adverse event include: presence of previous heart disease, use of glucocorticosteroids, arterial hypertension, hepatic and renal dysfunction, infections, hypervolemia, edema. High-risk patients receiving intensive immunosuppressive therapy, especially children, should have echocardiographic and ECG monitoring before and after transplantation (at 3 and 9-12 months). If abnormalities are detected, consideration should be given to reducing the dose of tacrolimus or replacing it with another immunosuppressant.

Tacrolimus may cause QT interval prolongation and pirouette-type heart rhythm disturbances (bidirectional spindle-shaped ventricular tachycardia). Caution should be exercised when treating patients with suspected or diagnosed congenital or acquired prolonged QT interval syndrome, as well as patients receiving drugs that prolong the QT interval, cause electrolyte disturbances or increase the concentration of tacrolimus in the blood. Consideration should also be given to patients with risk factors for QT interval prolongation, including patients with a personal or family history of QT interval prolongation, congestive heart failure, bradyarrhythmias, and electrolyte disturbances.

In patients taking tacrolimus, gastrointestinal perforation has been reported. Because gastrointestinal perforation is a medically significant event that can lead to a serious or life-threatening condition, immediate treatment measures should be initiated after signs or symptoms of perforation occur.

Patients taking tacrolimus may develop post-transplant lymphoproliferative disease (PTLD) associated with Epstein-Barr virus. Simultaneous use of tacrolimus with anti-lymphocyte antibodies (e.g., daclizumab, basiliximab) increases the risk of PTLD. Children younger than 2 years of age and children with a negative Epstein-Barr virus capsid antigen test are at high risk of developing PTLD. Therefore, serological testing for Epstein-Barr virus capsid antigen should be performed before prescribing Tacrolimus in this group of patients. Close monitoring for Epstein-Barr virus by polymerase chain reaction (PCR) is recommended during treatment. A positive PCR for Epstein-Barr virus can persist for months and is not in itself evidence of PTLD or lymphoma.

There have been reports of reversible posterior encephalopathy syndrome on tacrolimus therapy. If a patient taking tacrolimus presents with symptoms characteristic of reversible posterior encephalopathy syndrome: headache, mental disturbances, seizures, and visual disturbances, a radiologic examination, such as an MRI, should be performed. If the diagnosis is confirmed, blood pressure and seizures should be adequately controlled, and the systemic tacrolimus administration should be stopped immediately. If these measures are taken, the condition is completely reversible in most patients.

In patients receiving immunosuppressive therapy, including tacrolimus, there is an increased risk of opportunistic infections (caused by bacteria, fungi, viruses, protozoa). Among these infections, nephropathy associated with
BK-virus and JC-virus-associated progressive multifocal leukoencephalopathy (PML) are noted. These infections are often associated with profound immune system suppression and can lead to severe or fatal outcomes, which must be taken into account when making a differential diagnosis in patients who have signs of renal dysfunction or neurological symptoms on immunosuppressive therapy.

Partial red-cell bone marrow aplasia (RBCA) has been reported in patients receiving tacrolimus. All patients had risk factors for PCKA, such as the presence of parvovirus B19 infection, diseases or concomitant therapy associated with the possibility of PCKA.

Immunosuppressive therapy increases the risk of malignancies, particularly skin malignancies. It is recommended to limit insolation and UV exposure, wear appropriate clothing, and use sunscreens with a high protection factor. The risk of developing secondary cancer is unknown.

The capsules of Tacrolimus contain lactose; therefore special caution should be used when prescribing the drug in patients with rare hereditary diseases associated with lactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Influence on driving and operating machinery

Caution should be exercised when driving vehicles and operating potentially dangerous machinery. Tacrolimus may cause visual and neurological impairment, especially in combination with alcohol.

Contraindications

Side effects

Because of the characteristics of the underlying disease and the large number of medications used concomitantly after transplantation, the profile of adverse events of immunosuppressants is difficult to establish precisely.

Many of the adverse reactions presented below are reversible and/or reduced with dose reduction. Oral administration is associated with a lower risk of adverse reactions compared to intravenous tacrolimus. Within each frequency group, adverse events are presented in descending order of severity. The adverse events, classified by organs and systems, are listed below in descending order of frequency of occurrence: Very common (> 1/10), common (> 1/100 to < 1/10), infrequent (> 1/1000 to < 1/100), rare (> 1/10 000 to < 1/1 000), very rare (< 1/10 000), frequency unknown (there is not enough data to establish frequency).

Cardiac disorders:often: coronary coronary disorders, tachycardia; infrequent: Ventricular arrhythmias and cardiac arrest, heart failure, cardiomyopathies, ventricular hypertrophy, supraventricular arrhythmias, palpitations, abnormal ECG values, rhythm and heart rate and pulse disturbances; rare: pericardial effusion; very rare: abnormal changes on echocardiogram, prolongation of QT interval on electrocardiogram, pirouette-type heart rhythm disturbances (bidirectional spindle ventricular tachycardia).

Disorders of the blood and lymphatic system: frequently: anemia, leukopenia, thrombocytopenia, leukocytosis, decreased or increased hemoglobin and/or hematocrit levels, abnormalities in red blood cell count; infrequently: coagulopathies, deviations in coagulogram values, pancytopenia, neutropenia; rare: thrombotic thrombocytopenic purpura, hypothrombinemia; frequency unknown: partial red cell aplasia, agranulocytosis, hemolytic anemia.

Nervous system disorders: very common: tremor, headache; common: seizures, impaired consciousness, paresthesias and dysesthesias, peripheral neuropathies, dizziness, writing disorders, nervous system disorders; infrequent: Coma, central nervous system hemorrhage and cerebral circulation disorders, paralysis and paresis, encephalopathy, speech and articulation disorders, amnesia; rare: increased muscle tone; very rare: myasthenia gravis.

Visual disorders:often: blurred vision, photophobia, eye disease, visual disturbances; infrequently: cataracts; rarely: blindness.

Hearing organ and labyrinth disorders: frequent: tinnitus (ringing); infrequent: hearing loss; rare: neurosensory deafness; very rare: hearing disorders.

Disorders of the respiratory system, thorax and mediastinum: frequently:dyspnea, pulmonary parenchymal disorders, pleural effusion, pharyngitis, cough, nasal congestion, rhinitis; infrequently: respiratory failure, airway disorders, asthma; rarely: acute respiratory distress syndrome.

Gastrointestinal tract disorders:very often: diarrhea, nausea; frequently: gastrointestinal inflammatory disease, gastrointestinal ulcers and perforations, gastrointestinal bleeding, stomatitis and oral mucosal ulceration, ascites, vomiting, gastrointestinal and abdominal pain, dyspepsia, constipation, flatulence, abdominal bloating and distention feelings, liquid stool, symptoms of gastrointestinal tract disorders; infrequently: paralytic intestinal obstruction (paralytic ileus), peritonitis, acute and chronic pancreatitis, increased blood amylase levels, gastroesophageal reflux disease, disorders of gastric evacuation function; rare: subileus, pancreatic pseudocysts.

Renal and urinary tract disorders: very frequently: impaired renal function; frequently: 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 disorders:often: itching, rash, alopecia, acne, hyperhidrosis, infrequent: dermatitis, photosensitization, rarely: toxic epidermal necrolysis (Lyell syndrome), very rare: Stevens-Johnson syndrome.

Endocrine system disorders: rarely: hirsutism.

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

Immune system disorders:Allergic and anaphylactic reactions have been observed in patients taking tacrolimus.

Infectious and parasitic diseases: As with tacrolimus therapy, as with other immunosuppressants, the risk of localized and generalized infectious diseases (viral, bacterial, fungal, protozoal) increases. The course of previously diagnosed infectious diseases may worsen. Cases of BC-virus-associated nephropathy and progressive multifocal leukoencephalopathy (PML) associated with JC-virus have been observed on immunosuppressive therapy, including tacrolimus therapy.

Injuries, intoxications and complications of manipulation:often: primary graft dysfunction.

In practice, errors in the use of tacrolimus drugs have been observed, including unwarranted, unintentional or uncontrolled transfer of patients from one form of tacrolimus (standard or prolonged) to another, and related cases of graft rejection have been reported (the frequency cannot be estimated from the available data).

Benign, malignant and unspecified neoplasms (including cysts and polyps):Patients receiving immunosuppressive therapy have a higher risk of malignancy. Both benign and malignant neoplasms, including Epstein-Barr virus (EBV)-associated lymphoproliferative diseases and skin cancer, have been reported with tacrolimus.

General disorders and disorders at the site of administration:often: asthenia, fevers, edema, pain and discomfort, increased blood alkaline phosphatase activity, weight gain, body temperature perception disorders; infrequently: multi-organ failure, flu-like syndrome, impaired perception of ambient temperature, chest tightness sensation, anxiety, impaired well-being, increased blood lactate dehydrogenase activity, decreased body weight; rare: thirst, loss of balance (falls), feeling of stiffness in the chest, difficulty moving, ulceration; very rare: increased adipose tissue mass.

Hepatic and biliary tract disorders:often: increased liver enzymes, liver dysfunction, abnormal changes in liver function tests, cholestasis and jaundice, liver cell lesions and hepatitis, cholangitis; rarely: hepatic artery thrombosis, hepatic vein obliterating endophlebitis; very rare: liver failure, bile duct stenosis.

Gender and mammary gland disorders: infrequent: dysmenorrhea and uterine bleeding.

Mental disorders:very common: insomnia; common: anxiety, confusion and disorientation, depression, depressed mood, mood disorders, nightmares, hallucinations, psychotic disorders; infrequent: psychotic disorders.

Overdose

There are limited reports of overdose. Several episodes of accidental overdose have been reported in patients taking tacrolimus medication. Symptoms have included tremors, headache, nausea, vomiting, infections, urticaria, lethargy, elevated blood urea nitrogen, serum creatinine and alanine aminotransferase.

There are currently no antidotes to tacrolimus. In case of overdose, standard measures should be taken and symptomatic treatment should be administered. Given the high molecular weight of tacrolimus, poor water solubility and marked binding to red blood cells and plasma proteins, dialysis is ineffective. Hemofiltration or diafiltration were effective in individual patients with very high concentrations of tacrolimus in the blood. In cases of oral overdose, gastric lavage and/or administration of adsorbents (e.g., activated charcoal) may be effective if these measures are taken soon after taking the drug.

Similarities