Universal reference book for medicines

Active substance: tacrolimus

Type: Immunosuppressive drug

Manufacturer: DR.
Description of the active substance:
This information is a reference and it is not enough that the drug has been prescribed by a doctor ..

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, providing calcium-dependent blocking of T-cell signaling pathways and preventing the transcription of a discrete series of lymphokine genes.
Tacrolimus is a highly active immunosuppressant.
In experiments in vitro and in vivo, tacrolimus clearly reduced the formation of cytotoxic lymphocytes, which play a key role in the rejection reaction of the graft. Tacrolimus inhibits the formation of lymphokines (interleukin-2, interleukin-3,? -terferon), T cell activation, interleukin-2 receptor expression, and T-helper dependent proliferation of B cells.
Absorption of tacrolimus is variable (the variability of absorption in adult patients is 6-43%).
Bioavailability of tacrolimus 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.The distribution of tacrolimus in the human body after intravenous administration is biphasic. In the systemic circulation, tacrolimus binds well to erythrocytes. The ratio of tacrolimus concentrations in whole blood and plasma is about 20: 1. A significant fraction of plasma tacrolimus (> 98.8%) is in the state bound to plasma proteins (serum albumin,? 1- acid glycoprotein).
Tacrolimus is widely distributed in the body.
V d in the equilibrium state with allowance for plasma concentrations is about 1300 liters (in healthy people). The same indicator, calculated on whole blood, is on average 47.6 liters.
Tacrolimus has a 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 l / h, 6.7 l / h and 3.9 l / h, 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.
T 1/2 of tacrolimus is long and changeable.
In healthy people, the mean T 1/2 in whole blood is approximately 43 hours.
Tacrolimus is actively metabolized in the liver, mainly with the participation of the CYP3A4 isoenzyme.
Metabolism tacrolimus intensively flows in the intestinal wall. Several metabolites of tacrolimus have been identified. In vitro experiments, it was shown that only one of the metabolites has immunosuppressive activity close to that of tacrolimus. Other metabolites were characterized by weak immunosuppressive activity or lack of it. In the systemic circulation, only one of the metabolites of tacrolimus in low concentrations was detected. Thus, the pharmacological activity of tacrolimus is practically independent of metabolites.
After intravenous administration and oral administration of 14 C-labeled tacrolimus, the major portion of radioactivity was found in the feces.
Approximately 2% of radioactivity was recorded in urine. In urine and feces, about 1% was determined unchanged.
For systemic use: 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.
For external use: treatment of atopic dermatitis (moderate severity and severe forms) in case of insufficient response of patients to traditional methods of treatment or contraindications to such.

The dose and frequency of application are set individually, depending on the indications, the clinical situation and the dosage form used.

From the cardiovascular system: very often - myocardial ischemia, tachycardia, arterial hypertension, bleeding, thromboembolic and ischemic complications, violation of peripheral circulation, arterial hypotension;
infrequent ventricular arrhythmias and cardiac arrest, heart failure, cardiomyopathies, ventricular hypertrophy, supraventricular arrhythmias, palpitations, abnormal ECG, heart rhythm disturbances, heart rate and pulse, heart attack, deep vein thrombosis, shock; rarely - pericardial effusion; very rarely - echocardiogram disorders.
From the hemopoietic system: often - anemia, leukopenia, thrombocytopenia, leukocytosis;
infrequently - pancytopenia, neutropenia; rarely thrombotic thrombocytopenic purpura.
From the coagulation system of the blood: infrequently - coagulopathy, deviations in the coagulogram indices, rarely - hypoprothrombinemia.

From the side of the central nervous system: very often - tremor, headache, insomnia;
frequent epileptic seizures, impaired consciousness, paresthesia and dysesthesia, peripheral neuropathies, dizziness, violation of writing, anxiety, confusion and disorientation, depression, depressed mood, emotional disorders, nightmares, hallucinations, mental disorders; infrequently - coma, hemorrhages in the central nervous system and cerebral circulatory disorders, paralysis and paresis, encephalopathy, speech and articulation disorders, amnesia, psychotic disorders; rarely - increased muscle tone; very rarely - myasthenia gravis.
From the side of the organ of vision: often - blurred vision, photophobia, eye diseases;
infrequently - cataract; rarely - blindness.
From the side of the organ of hearing: often - noise (ringing) in the ears;
infrequently - hearing loss; rarely - sensorineal deafness; very rarely - hearing impairment.
On the part of the respiratory system: often - shortness of breath, pulmonary parenchymal disorders, pleural effusion, pharyngitis, cough, nasal congestion, rhinitis;infrequent - respiratory failure, respiratory tract disorders, asthma;
rarely acute respiratory distress syndrome.
From the digestive system: very often - diarrhea, nausea;
often - inflammatory diseases of the digestive tract, gastrointestinal ulcers and perforations, gastrointestinal bleeding, stomatitis and ulceration of the oral mucosa, ascites, vomiting, gastrointestinal and abdominal pain, indigestion, constipation, flatulence, sensations of bloating and swelling in the abdomen, liquid stool, symptoms of gastrointestinal disorders; infrequently - paralytic intestinal obstruction (paralytic ileus), peritonitis, acute and chronic pancreatitis, increased amylase level in the blood, gastroesophageal reflux disease, violation of the evacuation function of the stomach; rarely - subileus, pancreatic pseudocysts.
On the part of the liver: often - increased levels of liver enzymes, violations of liver function, cholestasis and jaundice, damage to liver cells and hepatitis, cholangitis;rarely - thrombosis of the hepatic artery, obliterating endophlebitis of the hepatic veins;
very rarely - liver failure, stenosis of the bile duct.
From the side of the urinary system: very often - impaired renal function;
often - renal failure, acute renal failure, oliguria, acute tubular necrosis, toxic nephropathy, urinary syndrome, disorders of the bladder and urethra; infrequently - anuria, hemolytic uremic syndrome; very rarely - nephropathy, hemorrhagic cystitis.
Dermatological reactions: often - itching, rashes, alopecia, acne, hyperhidrosis;
infrequently - dermatitis, photosensitivity; rarely - toxic epidermal necrolysis (Lyell's syndrome); very rarely - Stevens-Johnson syndrome.
From the musculoskeletal system: often - arthralgia, muscle cramps, pain in the extremities, back pain;
infrequently - articular disorders.
On the part of the endocrine system: very often - hyperglycemia, diabetes mellitus;
rarely - hirsutism.
From the side of metabolism: very often - hyperkalemia;
often hypomagnesemia, hypophosphatemia, hypokalemia, hypocalcemia, hyponatremia, hypervolemia, hyperuricemia, decreased appetite, anorexia, metabolic acidosis, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, electrolyte disturbances; infrequently - dehydration, hypoproteinemia, hyperphosphataemia, hypoglycemia.
Infections and invasions: against the background of therapy with tacrolimus, 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 VC virus, as well as progressive multifocal leukoencephalopathy.
Injuries, poisonings, complications of procedures: often - primary dysfunction of the transplant.

Benign, malignant and unidentified neoplasms: patients receiving immunosuppressive therapy have a higher risk of malignant tumors.
With the application of tacrolimus, the appearance of both benign and malignant neoplasms was noted, incl. Epstein-Barr virus-associated lymphoproliferative diseases and skin cancer.
On the part of the reproductive system: infrequently - dysmenorrhea and uterine bleeding.
The negative effect of tacrolimus on male fertility, expressed in a decrease in the number and mobility of spermatozoa, was found in rats.
Allergic reactions: all patients taking tacrolimus experienced allergic and anaphylactic reactions.

On the part of the body as a whole: often - asthenia, febrile conditions, swelling, pain and discomfort, increased blood levels of the alkaline phosphatase, weight gain, impaired body temperature perception;
infrequently - multiple organ dysfunction, flu-like syndrome, impaired perception of the temperature of the environment, a feeling of squeezing in the chest, a sense of anxiety, deterioration of well-being, increased LDH activity in the blood, weight loss; rarely - thirst, loss of balance (fall), a feeling of stiffness in the chest, difficulty moving; very rarely - an increase in the mass of adipose tissue.
For systemic and external use: pregnancy;
lactation period (breastfeeding); increased sensitivity to tacrolimus.
For external use: genetic defects of the epidermal barrier, such as the Netherton syndrome;
lamellar ichthyosis; skin manifestations of the "graft versus host" reaction;generalized erythroderma (due to the risk of a progressive increase in systemic absorption of tacrolimus); children and adolescents under 16 years (depending on the dosage form used).
Contraindicated in pregnancy and lactation (breastfeeding).

In the initial post-transplant period, the following parameters should be regularly monitored: blood pressure, ECG, neurological status and vision, fasting blood glucose, electrolyte concentration (especially potassium), hepatic and renal function, hematological parameters, coagulogram, proteinemia level.
In the presence of clinically significant changes, correction of immunosuppressive therapy is necessary.
During the application of tacrolimus, the administration of herbal preparations containing Hypericum perforatum should be avoided, as well as other herbal remedies that can reduce the concentration of tacrolimus in the blood and adversely affect the clinical effect of tacrolimus.

With diarrhea, the concentration of tacrolimus 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 cyclosporine.

When tacrolimus is used, cases of cardiomyopathy - ventricular hypertrophy or hypertrophy of the parturition of the heart are described.
In most cases, myocardial hypertrophy was reversible and was observed with tacrolimus concentrations in the blood exceeding those recommended. Other risk factors are: 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 tacrolimus or replacing it with another immunosuppressant.
Tacrolimus may induce prolongation of the QT interval.
In the treatment of patients with diagnosed congenital syndrome of an extended QT interval or suspected of such a condition, special care should be taken.
Patients receiving 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, before tacrolimus is used in this group of patients, a serological study should be conducted for the presence of the Epstein-Barr virus capsid antigen. 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 immunosuppressants, 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 deep suppression of the immune system and can lead to severe or fatal outcomes, which must be taken into account when making a differential diagnosis in patients with signs of impaired renal function or neurological symptoms with immunosuppressive therapy.
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.
There are reports of the occurrence of the syndrome of reversible posterior encephalopathy with tacrolimus therapy.
If the patient receiving tacrolimus has symptoms that are characteristic of the syndrome of reversible posterior encephalopathy (headache, mental disorders, seizures and visual disturbances), magnetic resonance imaging is necessary. When confirming the diagnosis, you should monitor blood pressure, the occurrence of seizures, and immediately stop the systemic administration of tacrolimus. If these measures are taken, this condition is completely reversible in most patients.
Use in Pediatrics

For external use, tacrolimus should be used in dosage forms appropriate to the child's age.

Impact on the ability to drive vehicles and manage mechanisms

Tacrolimus can cause visual and neurological disorders, especially in combination with alcohol.
During treatment, patients should refrain from driving vehicles and working with mechanisms.
After oral administration, tacrolimus undergoes a metabolism in the intestinal cytochrome CYP3A4 system.
Simultaneous intake of drugs or medicinal herbs with an established inhibitory or inducing action on CYP3A4 can respectively increase or decrease the concentration of tacrolimus in the blood.
Based on clinical experience, it was found that the tacrolimus concentration in the blood can be significantly increased by the following drugs: antifungal agents (ketoconazole, fluconazole, itraconazole, voriconazole), macrolide antibiotics (erythromycin), HIV protease inhibitors (ritonavir) (with this combination, tacrolimus).Pharmacokinetic studies have shown that an increase in tacrolimus concentration in the blood is primarily a consequence of increased bioavailability of tacrolimus when ingested 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 vitro studies, the following substances have been shown to be potential inhibitors of tacrolimus metabolism: bromocriptine, cortisone, dapsone, ergotamine, gestodene, lidocaine, mephenytoin, miconazole, midazolam, nilvadipine, norethinodrone, quinidine, tamoxifen, (triacetyl) oleandomycin.

It is recommended to avoid the use of grapefruit juice in connection with the possibility of increasing the level of tacrolimus in the blood.

Lansoprazole and cyclosporine can potentially inhibit CYP3A4-mediated metabolism of tacrolimus and increase its concentration in the blood.
It was found that the concentration of tacrolimus in the blood can significantly reduce these drugs on the basis of clinical experience: rifampicin, phenytoin, St. John's Wort (Hypericum perforatum).
Clinically significant interaction was observed with phenobarbital.
Corticosteroids in maintenance doses typically reduce the concentration of tacrolimus in the blood. High doses of prednisolone or methylprednisolone are used to treat acute rejection may increase or decrease the concentration of tacrolimus in the blood.
Carbamazepine, metamizole and isoniazid are capable of reducing the concentration of tacrolimus in the blood.
Tacrolimus inhibits CYP3A4 isoenzyme and with simultaneous reception may affect the drugs metabolized isoenzyme CYP3A4. T 1/2 cyclosporine while the use of tacrolimus is increased. Also, there may be synergistic / additive nephrotoxic effects. For these reasons, the simultaneous reception of cyclosporin and tacrolimus is not recommended, and for assigning tacrolimus patients who previously received cyclosporine, care must be taken.
Tacrolimus increases the concentration of phenytoin in blood.
Tacrolimus may reduce the clearance of hormonal contraceptives.
Experimental studies in animals have shown that tacrolimus has the potential to reduce the clearance and increase the T 1/2pentobarbital and antipyrine.
The bioavailability of tacrolimus can increase prokinetic agents (metoclopramide, cisapride), cimetidine, aluminum hydroxide and magnesium.
The simultaneous use of tacrolimus with drugs possessing nephrotoxicity and neurotoxicity (e.g., aminoglycosides, gyrase inhibitors, vancomycin, trimethoprim-sulfamethoxazole, NSAIDs, ganciclovir, acyclovir), may contribute to these effects.
As a result, the joint use of tacrolimus with amphotericin B and ibuprofen amplification nephrotoxicity observed.
Tacrolimus can promote or enhance hyperkalemia (potassium simultaneous use should be avoided or potassium-sparing diuretics in high doses).
Immunosuppressive drugs can alter the body's response to vaccination. Vaccination tacrolimus treatment period can be less effective. It should avoid the use of live attenuated vaccines.
Tacrolimus avidly binds to plasma proteins. It is possible to consider tacrolimus competitive interaction with drugs having a high affinity to plasma proteins (NSAIDS, oral anticoagulants, oral hypoglycemic agents).
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