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

Excipients: Hypromellose (E-5) 0.400 mg, hypromellose (E-15) 0.300 mg, anhydrous lactose 82.939 mg, croscarmellose sodium 0.250 mg, magnesium stearate 0.60 mg.

Capsule shell composition: (gelatin q.s. up to 100%, titanium dioxide (E 171) 0.3375 mg, iron oxide dye yellow (E 172) 0.0479 mg) 28.0 mg.

Composition of red paint TeckPrint^TM SB-1033 Red Ink: Shellac 23-30%, anhydrous ethanol 34-40%, isopropanol 0.5-6%, butanol 0.5-6%, propylene glycol 2-10%, concentrated ammonia solution 1-2%, iron dye red oxide (E 172 ) 16-22%.

Each capsule with a dosage of 1 mg contains:

Active substance:

Tacrolimus monohydrate 1,022 mg equivalent to tacrolimus 1.0 mg

Excipients: Hypromellose (E-5) 0.800 mg, hypromellose (E-15) 0.600 mg, anhydrous lactose 81.478 mg, croscarmellose sodium 0.500 mg, magnesium stearate 0.60 mg.

Capsule shell composition: (gelatin q.s. to 100%, titanium dioxide (E 171) 0.3375 mg) 28.0 mg.

Each capsule with a dosage of 5 mg contains:

Active substance:

Tacrolimus monohydrate 5.11 mg equivalent to tacrolimus 5.0 mg

Excipients: Hypromellose (E-5) 4.00 mg, hypromellose (E-15) 3.00 mg, anhydrous 124.39 mg, croscarmellose sodium 2.50 mg, magnesium stearate 1.0 mg.

Capsule shell composition: (gelatin q.s. up to 100%, titanium dioxide (E 171) 0.73 mg, ferric oxide red oxide (E 172) 0.07 mg, technological additive * 0.06 mg) 40.0 mg

* The composition of the technological additive includes sodium lauryl sulfate and sorbitan laurate in a ratio of 1: 1.

Description:

Capsules with a dosage of 0.5 mg: Hard gelatin capsules number 5, body and cap - light yellow color. Inscription on the cap "PanGraf", on the body - "0.5" red. The contents of the capsules are a granular powder of white or almost white color.

Capsules with a dosage of 1 mg: Hard gelatin capsules number 5, body and cap - white. Inscription on the cap "PanGraf", on the case - "1.0" red. The contents of the capsules are a granular powder of white or almost white color.

Capsules with a dosage of 5 mg: Hard gelatin capsules number 4, body and cap - pink. Inscription on the cap "PanGraf", on the case - "5.0" red. The contents of the capsules are a granular powder of white or almost white color.

Pharmacotherapeutic group:Immunosuppressive agent - calcineurin inhibitor

Pharmacodynamics:

Tacrolimus has a strong inhibitory effect on the activation of T-lymphocytes.It binds to immunophilins FK 506-binding proteins (FKBP-12), as a result of which a complex of FKBP-12, calcium, calmodulin and calcineurin, which inhibits the phosphate activity of calcineurin. This results in blockade of dephosphorylation and translocation of the nuclear factor of activated T-lymphocytes (NFAT) and inhibits the transcription of the early activation gene for T lymphocytes, interleukin-2, tumor necrosis factor (TNF-α) and protooncogenes, and also inhibits the expression of interleukin-2 and 7 receptors. As a result of all these processes, activation of T lymphocytes is inhibited. Tacrolimus inhibits the production of cytotoxic T-lymphocytes and T-lymphocyte-dependent activation of B lymphocytes.

Pharmacokinetics:

Absorption

Tacrolimus is absorbed from the gastrointestinal tract (GIT); the main place of absorption is the upper gastrointestinal tract.

When administered orally, the mean time to reach the maximum concentration (Tc_m_Oh) tacrolimus in the blood is 1-3 hours Bioavailability when taking the drug inside is an average of 20-25%. After oral administration (0.3 mg / kg / day) of the drug in patients with liver transplant in most patients, equilibrium concentrations of tacrolimus were achieved within 3 days.

In studies involving healthy volunteers, the bioequivalence of the Pangraf® capsules was 0.5 mg, 1 mg, and 5 mg when taken in equal doses.

The highest rate and degree of absorption of tacrolimus is achieved when taking the drug on an empty stomach. The speed and extent of absorption of tacrolimus while taking with food are reduced, especially in the case of high levels of fat in the diet. The influence of foods rich in carbohydrates on the absorption of tacrolimus is less pronounced. In patients with a liver transplant in a stable state, the bioavailability of tacrolimus was reduced by oral administration of the drug after a moderate-fat meal. There was also a decrease in the area under the pharmacokinetic curve "concentration-time" (AUC) (27%), the maximum concentration (C_m_Oh) (50%) and an increase in Tc_m_Oh (173%) in whole blood.

In stable patients after kidney transplantation, when taking the drug immediately after a standard breakfast, the effect of food on the bioavailability of tacrolimus was less pronounced. There was a decrease AUC (by 2-12%) and C_m_Oh (by 15-38%), and an increase in Tc_m_Oh (by 38-80%).

Isolation of bile does not affect the absorption of tacrolimus.

On the background of drug therapy, when an equilibrium state is reached, a high correlation is observed between AUC and minimum concentrations of tacrolimus in whole blood. Therefore, monitoring the minimum concentrations of tacrolimus in whole blood can serve as a method that provides an adequate assessment of the systemic exposure of tacrolimus.

Distribution

In the systemic circulation tacrolimus largely associated with erythrocytes. The ratio of tacrolimus concentrations in whole blood and plasma is approximately 20: 1. In the blood plasma tacrolimus is largely bound (> 98.8%) to proteins, mainly with serum albumin and α-1-acid glycoprotein.

Tacrolimus is widely distributed in the body. The equilibrium volume of distribution based on plasma concentrations is approximately 1300 liters (healthy volunteers). The corresponding indicator based on whole blood, on average, is 47.6 liters. Tacrolimus is a preparation with a low level of clearance. In healthy volunteers, the average value of total clearance, estimated by tacrolimus concentrations in whole blood, was 2.25 l / h.In adult patients with liver, kidney and heart transplant, the values of this parameter were 4.1 l / h, 6.7 l / h and 3.9 l / h, respectively. In children with a liver transplant, the overall clearance value is approximately 2 times higher than in adult patients with a liver transplant. Low hematocrit and hypoproteinemia contribute to an increase in the unbound fraction of tacrolimus, accelerating the clearance of tacrolimus.

The half-life (T_1/2) tacrolimus is long and variable. In healthy volunteers, the mean T_1/2 of whole blood is approximately 43 hours. In adult patients and children with liver transplant T_1/2an average of 11.7 hours and 12.4 hours, respectively, compared with 15.6 hours in adult patients with a kidney transplant.

Metabolism

Tacrolimus is actively metabolized in the liver, mainly by isoenzyme 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 is practically independent of metabolites.

Excretion

After taking tacrolimus labeled ¹⁴With the isotope, most of the radiolabeled drug was excreted by the intestine. Approximately 2% is excreted by the kidneys, while about 1% of tacrolimus was determined unchanged. Consequently, tacrolimus before elimination almost completely metabolized, the main way of elimination was bile.

Indications:

Prevention of rejection reaction of liver, kidney or heart allograft. Treatment of allograft rejection reaction, resistant to other regimens of immunosuppressive therapy.

Contraindications:

Deficiency of lactase, lactose intolerance, glucose-galactose malabsorption. Tacrolimus is contraindicated in patients with hypersensitivity to it and other components of the drug, macrolides.

Pregnancy and lactation:

Pregnancy: Tacrolimus 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, this drug should not be administered to pregnant women, unless the intended benefit of treatment for the mother justifies 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 function of the kidneys).

Breast-feeding: tacrolimus penetrates into breast milk, and therefore women receiving this drug should cancel breastfeeding.

Dosing and Administration:

Basic instructions

Tacrolimus therapy requires careful monitoring by personnel with the appropriate qualifications and who have the necessary equipment at their disposal. Prescribe or change the immunosuppressive therapy only by physicians with experience of immunosuppressive therapy in patients with transplanted organs.

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.

If you miss taking capsules tacrolimus must take the next dose in time. A double dose of the drug should not be taken.

General Provisions

The initial doses presented below should only be considered as recommendations. In the initial postoperative period tacrolimus usually used in combination with other immunosuppressants. The dose may vary depending on the regimen of immunosuppressive therapy. The choice of tacrolimus dose should be based, first of all, on a clinical assessment of the risk of rejection and individual drug tolerance, as well as on the monitoring of tacrolimus concentration in the blood.

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

Tacrolimus in the capsule dosage form is administered orally; If necessary, the contents of the capsules can be mixed with water and injected through a nasogastric tube.

The dose is selected individually, depending on the concentration of the drug in the blood. It is recommended to divide the daily dose into 2 doses (in the morning and in the evening). Capsules should be taken immediately after removing them from the blister pack, swallowed whole, squeezed with liquid (preferably water). To achieve maximum absorption, capsules are recommended to be taken on an empty stomach, 1 hour before or 2-3 hours after eating.

If necessary, the contents of the capsules can be dissolved in water and injected through a nasogastric tube. Children up to 3 years of age should take the drug, after opening the capsule and mixing its contents with water.

In the initial postoperative period tacrolimus usually taken with other immunosuppressive drugs. The dose of tacrolimus can vary depending on the chosen mode of immunosuppression.

Duration of admission

To prevent rejection of the transplant, immunosuppressive therapy should be performed; Consequently,the duration of oral therapy is not limited.

Recommendations for dosing - liver transplantation

Prevention of graft rejection the adults: orally, 0.10-0.20 mg / kg / day, divided into two doses. The drug should be started 12 hours after the operation is completed.

Prevention of graft rejection the children: orally, 0.30 mg / kg / day, divided into two doses.

If the patient's clinical condition does not allow him to take the medicine inside, infusion therapy with tacrolimus should be started.

Supportive therapy adults and children: the dose is usually reduced; in some cases tacrolimus can be used as a basic monotherapy (cancellation of concomitant immunosuppressive drugs). Improving the patient's condition after transplantation can alter the pharmacokinetics of tacrolimus, which may require dose adjustment.

Treatment of rejection reaction the adults and children: higher doses of tacrolimus should be used in combination with glucocorticosteroids and short courses of mono / polyclonal antibodies. In case of signs of toxicity, it may be necessary to reduce the dose of tacrolimus.

Dosing recommendations - kidney transplantation

Prevention of graft rejection the of adults: orally - 0.20-0.30 mg / kg / day, dividing it into two doses. The drug should be started approximately 24 hours after the operation is completed. If the patient's condition does not allow taking the medication internally, intravenous therapy should be started from a dose of 0.05-0.10 mg / kg / day as a continuous 24-hour infusion.

Prevention of graft rejection the children: orally - 0.30 mg / kg / day, divided into two doses.

If the clinical condition of the patient does not allow taking medicines inward, then it is necessary to start iv / therapy with tacrolimus in the form of a solution for infusions.

Supportive therapy adults and children: the dose is usually reduced; In some cases, it is possible to cancel concomitant immunosuppressants, leaving tacrolimus as a basic component of dual therapy. Improving the patient's condition after transplantation can alter the pharmacokinetics of tacrolimus, which may require dose adjustment.

Treatment of graft rejection in adults and children: higher doses of tacrolimus should be used in combination with glucocorticosteroids and short courses of mono / polyclonal antibodies. In case of signs of toxicity, it may be necessary to reduce the dose of tacrolimus.

Dosing recommendations - heart transplantation

Tacrolimus can be used in combination with induction therapy with antibodies or in patients whose condition is stable without the introduction of antibodies.

Prophylaxis of graft rejection in adults: With the concomitant administration of antibodies: orally - 0.075 mg / kg / day, divided into two doses. The drug should be started within 5 days after the operation is completed, as soon as the patient's condition is stabilized.

An alternative strategy is to start taking tacrolimus approximately 12 hours after transplantation. This approach is intended for patients without signs of impaired function of internal organs (eg, kidneys). In this case, the initial dose of tacrolimus is 2-4 mg per day in combination with mycophenolate mofetil and glucocorticosteroids or in combination with sirolimus and glucocorticosteroids.

Prevention of graft rejection the children:

In those cases when induction is not carried out with antibodies and tacrolimus injected IV in the form of a solution for infusions, the recommended initial dose is 0.03-0.05 mg / kg / day as a continuous 24-hour infusion to achieve a tacrolimus concentration in whole blood of 15-25 ng / ml.At the first clinical opportunity, the patient should be transferred to the oral administration of the drug. The initial dose for oral administration should be 0.30 mg / kg / day and should be administered 8-12 hours after discontinuation of intravenous infusion. With the concomitant administration of antibodies: orally - 0.10-0.30 mg / kg / day, divided into two doses.

Supportive therapy adults and children: the dose is usually reduced. Improving the patient's condition after transplantation can alter the pharmacokinetics of tacrolimus, which may require dose adjustment.

Treatment of graft rejection reaction the adults and children: higher doses of tacrolimus should be used in combination with glucocorticosteroids and short courses of mono / polyclonal antibodies. Adults transferred to tacrolimus: orally - 0.15 mg / kg / day, divided into two doses. Children transferred to tacrolimus: orally - 0.20-0.30 mg / kg / day, divided into two doses.

Recommended doses for treatment of rejection after allotransplantation of other organs

Recommendations for dosing Prograf® for patients after lung, pancreas and small intestine allotransplantation are based on data from selected prospective clinical trials. After lung transplantation tacrolimus is used in the initial dose of 0.10-0.15 mg / kg / day, pancreas allotransplantation - at an initial dose of 0.2 mg / kg / day. In patients after small intestinal allotransplantation, the initial dose of the drug is 0.3 mg / kg / day.

Correction of the dosing regimen for special categories of patients

Patients with hepatic insufficiency.

Dose reduction may be required for patients with severe impairment of liver function to maintain tacrolimus concentration in the blood within the recommended target value.

Patients with renal insufficiency.

Since renal function does not affect the pharmacokinetics of tacrolimus, dosage adjustment is not required. However, due to the presence of nephrotoxic action in tacrolimus, it is recommended to carefully monitor the kidney function (including the concentration of serum creatinine, creatinine clearance and diuresis).

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

Currently, there is no data on the need to adjust the dose of the drug in elderly patients.

Transfer from therapy with cyclosporin to tacrolimus.

Simultaneous use of drugs of cyclosporine and tacrolimus may increase the half-life of cyclosporine and enhance toxic effects. Therefore, care must be taken when transferring patients from cyclosporine to tacrolimus therapy. Tacrolimus therapy should be started after the determination the concentration of cyclosporine in the blood plasma and the clinical state of the patient. The use of the drug should be postponed if there is an increased concentration of cyclosporine. In practice, treatment is started 12-24 h after cessation of cyclosporine. After the transition, the concentration of cyclosporin in the blood should continue to be controlled, since the clearance of cyclosporine can be impaired.

Recommendations for monitoring the therapeutic concentration of tacrolimus in the blood

Dose choice tacrolimus is based on clinical assessment of rejection and drug tolerability in each individual patient. To optimize dosing, tacrolimus concentration in whole blood is measured using immune methods, including semi-automatic enzyme-linked immunosorbent assay (MIFA).Comparison of data on the concentration of tacrolimus in the blood published in the literature with individual clinical indicators should be conducted with caution and based on knowledge and understanding of the valuation method used.

In the postoperative period, it is important to monitor the minimum concentrations of tacrolimus in whole blood. To determine the minimum concentrations of tacrolimus in the blood, it is necessary to obtain blood samples 12 hours after taking the drug, immediately before the next dose. The frequency of tacrolimus concentration in the blood should depend on clinical needs. Tacrolimus is a preparation with a low clearance value, so after correction of the dose, the time to reach the equilibrium minimum concentration of tacrolimus in the blood can be several days. The minimum concentration of tacrolimus in the blood should be monitored approximately 2 times per week during the early post-transplant period and then periodically during maintenance therapy. The minimum concentration of tacrolimus in the blood should also be monitored after changing the dose of the drug,the regime of immunosuppression or after joint application with drugs that affect the concentration of tacrolimus in whole blood.

The results of clinical studies indicate that the treatment with capsules tacrolimus is most successful in those cases when the minimum concentration of tacrolimus in the blood does not exceed 20 ng / ml. When interpreting data on the concentration of tacrolimus in whole blood, it is important to assess the clinical state of the patient.

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

Side effects:

Many of the side effects listed below are reversible and / or are dose-dependent. With oral administration, fewer side effects occur than with intravenous administration. Below are the side effects, depending on the frequency of occurrence: very often (≥ 1/10), often (from ≥ 1/100 to <1/10), infrequently (from ≥ 1/1000 to <1/100), rarely ( from ≥ 1/10 000 to <1/1 000),very rarely (<1/10 000), the frequency is unknown (to establish the frequency of which, the data is not enough).

Heart Disease:

often: coronary artery ischemia, tachycardia;

infrequent: ventricular arrhythmia and cardiac arrest, heart failure, cardiomyopathy, ventricular hypertrophy, supraventricular arrhythmia, palpitations, abnormalities in ECG parameters, heart rate and pulse rate abnormalities;

rarely: exudative pericarditis;

very rarely: abnormal echocardiogram; interval lengthening QT, violation of the rhythm of the heart such as "pirouette."

Violations from the blood and lymphatic system:

often: anemia, leukopenia, thrombocytopenia, leukocytosis, a decrease or increase in hemoglobin and / or hematocrit; erythrocyte pathology;

infrequently: coagulopathy, bleeding disorders, insufficiency hematopoietic system, incl. pancytopenia, neutropenia;

rarely: thrombotic thrombocytopenic purpura, hypoprothrombinemia;

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

Impaired nervous system:

very often: tremor, headache;

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

rarely: increased muscle tone;

very rarely: myasthenia gravis.

Disorders from the side of the organ of vision:

often: blurred vision, photophobia, eye diseases;

infrequently: cataract;

rarely: blindness.

Hearing impairment:

often: noise (ringing) in the ears;

infrequently: hearing loss;

rarely: sensorineal deafness;

very rarely: hearing impairment.

Disturbances from the respiratory system and mediastinum:

often: dyspnea, pulmonary parenchymal disorders, pleural effusion, pharyngitis, cough, nasal congestion, rhinitis;

infrequent: respiratory failure, respiratory tract disorders, asthma;

rarely: acute respiratory distress syndrome.

Disorders from the gastrointestinal tract:

very often: diarrhea, nausea;

often: 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 rasping in the abdomen, loose stool, symptoms of disorders of the gastrointestinal tract;

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

rarely: subileus, pancreatic pseudocysts.

Disorders from the liver and bile ducts:

often: changes in hepatic enzyme activity, liver dysfunction, cholestasis, jaundice, liver cell damage, hepatitis, cholangitis;

rarely: thrombosis of the hepatic artery, obliterating endophlebitis of the hepatic veins; very rarely: hepatic insufficiency, stenosis of the bile duct.

Disorders from the kidneys and urinary tract:

very often: impaired renal function;

often: renal failure, including acute renal failure, oliguria, acute tubular necrosis, toxic nephropathy, urinary syndrome, disorders with the sides of the bladder and urethra;

infrequently: anuria, hemolytic uremic syndrome;

very rarely: nephropathy, hemorrhagic cystitis.

Disturbances from the skin and subcutaneous tissue:

often: itching, rashes, alopecia, acne, hyperhidrosis;

infrequently: dermatitis, photosensitivity;

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

very rarely: Stevens-Johnson syndrome.

Disturbances from the musculoskeletal and connective tissue:

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

infrequently: joint disease.

Disorders from the endocrine system:

rarely: hirsutism.

Disorders from the metabolism and nutrition:

very often: hyperglycemia, diabetes, hyperkalemia;

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

infrequently: dehydration, hypoproteinemia, hyperphosphataemia, hypoglycemia.

Infectious and parasitic diseases:

In patients receiving tacrolimus, as in the treatment with other immunosuppressive drugs, the risk of developing infectious diseases (viral, bacterial, fungal, protozoal) is increased. The course of previously diagnosed infectious diseases may worsen.

Cases of VK virus-associated nephropathy, as well as cases of progressive multifocal leukoencephalopathy (PML) associated with JCvirus, in patients receiving immunosuppressants, including tacrolimus.

Trauma, intoxication and complications of manipulation:

often: primary transplant dysfunction.

There have been cases of errors in the use of tacrolimus preparations, including unreasonable, unintentional or uncontrolled transfer of patients from one tacrolimus dosage form (standard or prolonged) to another. There are reports that some of these cases have been associated with transplant rejection (it is not possible to estimate the frequency of occurrence according to available data).

Benign, malignant and unidentified neoplasms (including cysts and polyps):

Patients receiving immunosuppressive therapy are at increased risk of developing malignant neoplasms. When tacrolimus was used, benign as well as malignant tumors were recorded, including the Epstein-Barr virus (EBV) -Associated lymphoproliferative diseases and malignant neoplasms of the skin.

Vascular disorders:

very often: arterial hypertension;

often: bleeding, thromboembolism and ischemic disorders, peripheral cardiovascular disorders, arterial hypotension;

infrequently: myocardial infarction, deep vein thrombosis of the extremities, shock.

General disorders and disorders at the site of administration:

often: asthenic conditions, febrile conditions, edema, pain and discomfort, increased alkaline phosphatase activity in the blood, increased body weight, impaired body temperature perception;

infrequently: multiple organ failure, influenza-like syndrome, disorders perception of the temperature of the environment, a feeling of squeezing in the chest, a sense of anxiety, deterioration of health, increased lactate dehydrogenase activity in the blood, weight loss;

rarely: a feeling of thirst, loss of balance (falling), a feeling of stiffness in the pectoral cell, obstruction of movement; ulcer;

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

Immune system disorders:

In patients receiving tacrolimus, allergic and anaphylactic reactions were observed.

Violations of the genitals and mammary glands:

infrequently: dysmenorrhea and uterine bleeding

Disorders of the psyche:

very often: insomnia;

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

infrequently: psychotic disorders.

Overdose:

Information on overdose is limited. Several episodes of overdose have been reported in patients taking tacrolimus medications. Symptoms: tremor, headache, nausea, vomiting, infection, urticaria, lethargy, increased blood urea nitrogen concentration and hypercreatininaemia, increased activity of alanine aminotransferase.

Treatment: symptomatic; after oral administration - gastric lavage and / or intake of adsorbents (Activated carbon). It is assumed that tacrolimus is not removed from the body in any significant amounts by hemodialysis. There is no specific antidote. In individual patients (with a very high concentration of the drug in the blood plasma), hemofiltration and diafiltration were effective, reducing the toxic concentrations of tacrolimus. The clinical experience of overdose management is limited.

Interaction:

Metabolic interactions

Tacrolimus is metabolized by isoenzyme CYP3A4. Simultaneous reception of medicines, incl. medicinal plants known for their inhibiting or inducing isoenzyme CYP3A4, can affect the metabolism of tacrolimus and thus increase or decrease the concentration of tacrolimus in the blood. Therefore, it is recommended to monitor the concentration of tacrolimus in the blood.

Inhibitors of Metabolism

Clinically proven that the following substances increase the concentration of tacrolimus in the blood:

Strong interactions were observed with antifungal agents (ketoconazole, fluconazole, itraconazole and voriconazole), macrolides (erythromycin), HIV protease inhibitors (incl. ritonavir, nelfinavir, saquinavir) or hepatitis C protease inhibitors (telaprevir, boceprevir). Simultaneous administration of tacrolimus with these drugs may require a reduction in the dose of tacrolimus.

Weaker interactions were observed with clotrimazole, clarithromycin, josamycin, nifedipine, nicardipine, diltiazem, verapamil, amiodarone, danazol, ethinyl estradiol, omeprazole and nefazodone.

In vitro the following drugs showed themselves as potential inhibitors of tacrolimus metabolism: bromocriptine, cortisone, dapsone, ergotamine, gestodene, lidocaine, mephenytoin, miconazole, midazolam, nilvadipine, norethisterone, quinidine, tamoxifen, troleandomycin.

It has been reported that the concentration of tacrolimus in the blood increases with the use of grapefruit juice, it is recommended to avoid their joint intake.

Lansoprazole and ciclosporin can potentially inhibit the CYPZA4-mediated metabolism of tacrolimus and increase its concentration in the blood.

Inductors of metabolism

Clinically proven that the following substances reduce the concentration of tacrolimus in the blood:

Strong interactions were observed with rifampicin, phenytoin, St. John's wort perforated.The simultaneous administration of tacrolimus with these drugs requires an increase in the dose of tacrolimus. Clinically significant interactions were observed with phenobarbital. Supportive doses of glucocorticosteroids reduce the concentration of tacrolimus in the blood.

High doses of prednisolone and methylprednisolone, used to treat acute graft rejection, contribute to a decrease or increase in tacrolimus concentration in the blood.

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

Effect of tacrolimus on the metabolism of other drugs

Tacrolimus is an inhibitor of the isoenzyme CYP3A4, therefore, simultaneous administration of tacrolimus with drugs metabolized by the isoenzyme CYP3A4, can affect the metabolism of these drugs.

Increases the half-life of cyclosporine, with the possible increase in toxic effects. It is not recommended simultaneous administration of cyclosporine and tacrolimus in patients who received early ciclosporin. Synergistic / additive nephrotoxic effects may also occur. It is advisable to use caution when transferring patients from cyclosporine to tacrolimus therapy (the concentration of cyclosporin in the blood should be monitored).

Tacrolimus increases the concentration of phenytoin in the blood plasma.

As tacrolimus can reduce the clearance of hormonal contraceptives, thus leading to an increase in the impact of these drugs, this should be taken into account when selecting methods of contraception.

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.

Preclinical data show that tacrolimus can potentially reduce the clearance and increase the half-life of pentobarbital and phenazone.

Metoclopramide, cisapride, cimetidine, magnesium hydroxide and aluminum hydroxide increase the concentration of tacrolimus in the blood.

Other interactions that lead to side effects

The simultaneous administration of tacrolimus with neuro- and nephrotoxic drugs (including aminoglycosides, gyrase inhibitors, vancomycin, sulfamethoxazole + trimethoprim, nonsteroidal anti-inflammatory drugs, ganciclovir, acyclovir) increases the risk of neuro- and nephrotoxicity.

Amphotericin B, ibuprofen increase the risk of developing tacrolimus nephrotoxicity. The risk of developing hyperkalemia increases with simultaneous use with K⁺ and potassium-sparing diuretics (including 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.

Due to the high degree of binding to plasma proteins tacrolimus possible competitive interaction with other drugs with high affinity to plasma proteins (including anti-inflammatory drugs, anticoagulants for oral administration, hypoglycemic agents for oral administration).

Special instructions:

In the initial post-transplant period should be carried out regularly monitors the following parameters: blood pressure, ECG, neurologic status and condition of view, fasting blood glucose level, the concentration of electrolytes (especially potassium), liver and kidney function, hematology, coagulation, proteinemii level.In the presence of clinically significant changes, correction of immunosuppressive therapy is necessary.

In practice, there were errors in the use of the drug tacrolimus, including unreasonable, unintentional or uncontrolled transfer of patients from one tacrolimus dosage form (standard or prolonged) to another. This led to serious adverse events, including graft rejection, or other side effects that could result from hypo- or hyperimmunosuppression caused by clinically significant differences in tacrolimus exposure. Patients should be on therapy with a single tacrolimus dosage form with an appropriate daily dosage regimen; the change in dosage form or dosage regimen should only be carried out under close supervision of a specialist in the field of transplantology.

In the case of simultaneous use with drugs that are inhibitors CYP3A4 (eg, telaprevir, boceprevir, ritonavir, ketoconazole, voriconazole, itraconazole, telithromycin or clarithromycin) or inductors CYP3A4 (eg, rifampicin, rifabutin) - the concentration in the blood of tacrolimus should be monitored for the purpose of timely dose adjustment.

Use of herbal preparations containing St. John's wort (St. John's wort) or other herbal preparations in the treatment of tacrolimus should be avoided because of the risk of their possible interaction, which leads to a decrease in blood concentrations of tacrolimus and a decrease in the clinical effect of tacrolimus.

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

Joint use of cyclosporine and tacrolimus should be avoided, with the appointment of tacrolimus to patients who have previously received ciclosporin.

Cases of ventricular hypertrophy or cardiac hypertrophy reported as cardiomyopathy were observed in patients taking tacrolimus. In most cases, myocardial hypertrophy was reversible. Other factors that increase the risk of this unwanted phenomenon include: the presence of a previous heart disease, the use of glucocorticosteroids, hypertension, impaired renal and hepatic function, infections, hypervolemia, edema.Patients with high risk and receiving intensive immunosuppressive therapy, especially children, 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 medicines containing tacrolimus or substituting them for another immunosuppressant.

The application of tacrolimus may lead to lengthening of the interval QT, but at the same time there is no evidence of the development of "pirouette tachycardia" (torsades de pointes). Caution should be exercised in patients with diagnosed or suspected congenital syndrome receiving drugs that extend the interval QT, causing electrolyte disturbances or increasing the concentration (exposure) of tacrolimus blood. Attention should also be paid to patients with risk factors for lengthening the interval QT, including patients with episodes of lengthening the interval QT in an individual or family anamnesis, congestive heart failure, bradyarrhythmias and electrolyte disorders.

Perforation of the gastrointestinal tract was noted in patients receiving tacrolimus. Since perforation of the gastrointestinal tract is a medically significant event that can lead to serious or life-threatening condition, after the appearance of signs or symptoms of perforation, it is necessary to immediately begin treatment activities.

Patients treated with tacrolimus may develop post-transplant lymphoproliferative diseases (PTLZ) associated with the Epstein-Barr virus. With simultaneous application of tacrolimus with antilymphocytic antibodies (for example, daclizumab, basiliximab) the risk of PTFE increases. There is also evidence of an increased risk of PTFE in patients with the Epstein-Barr virus capsid antigen. Children who are negative to the Epstein-Barr virus are negative, younger children (<2 years) have an increased risk of developing lymphoproliferative diseases. Therefore, before the appointment of the drug tacrolimus 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 several months and is not itself a sign of PTLZ or lymphoma.

In patients who received tacrolimus, there was a development of the syndrome of posterior reversible encephalopathy (ZOE). If patients taking tacrolimus, symptoms that indicate an SOE syndrome, such as headache, changes in mental state, convulsions, and visual impairment, should be identified (eg, MRI). If the SOE syndrome is confirmed, it is recommended that blood pressure control be performed and the tacrolimus is immediately discontinued. Most patients recover completely after appropriate measures.

Patients receiving immunosuppressive therapy, including tacrolimus, have an increased risk of opportunistic infections (bacterial, fungal, viral and protozoal). Among these infections, there is nephropathy associated with BV virus, and associated with JC-virus progressive multifocal leukoencephalopathy (PML). These infections are often associated with a deep suppression of the immune system and can lead to severe andfatal 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.

Cases of partial red cell aplasia of the bone marrow (PCCA) in patients who received tacrolimus.

All patients had risk factors for PKA, such as the presence of parvovirus B19 infection, disease or concomitant therapy associated with the possibility of developing PKA.

Immunosuppressive therapy increases the risk of malignant neoplasms, in particular, malignant skin diseases. 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.

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

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

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

Tacrolimus can cause visual and neurological disorders. Patients who developed such disorders should not drive a car or work with mechanisms.

Form release / dosage:

Capsules of 0.5 mg, 1 mg, 5 mg.

Packaging:

10 capsules per blister of aluminum foil or 100 capsules in a transparent bottle of high-density polyethylene with a screw cap made of polypropylene with protection from opening by children and a built-in dehumidifier.

For 5, 6 or 10 blisters with instructions for use in a pack of cardboard.

Each bottle in a cardboard box with instructions for medical use.

Storage conditions:

In dry, dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use the drug after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003404

Date of registration:12.01.2016

The owner of the registration certificate:Panacea Biotech Co., Ltd.Panacea Biotech Co., Ltd. India

Manufacturer: & nbsp

PANACEA BIOTEC, Ltd. India

Representation: & nbspKORAL-MED, CJSCKORAL-MED, CJSC

Information update date: & nbsp29.02.2016

Illustrated instructions

Instructions

Pangraph® (Pangraf®)