Redesp - instructions for use, doses, side effects, contraindications

Composition:Each 0.5 mg capsule contains: Active ingredient: tacrolimus 0.5 mg. Auxiliary substances: hypromellose 0.5 mg, lactose monohydrate 135 mg, v roscarmellose sodium 2.5 mg, magnesium stearate 1.5 mg.The composition of capsules of gelatinous solid size No. 4: sodium lauryl sulfate 0.08%, water 14.50%, titanium dioxide (E171), 4625%, iron dye red oxide (E172) 0.0060%, iron dye oxide yellow (E172) 0 , 3600%, gelatin 83.59%. Each 1.0 mg capsule contains: Active ingredient: tacrolimus 1.0 mg. Auxiliary substances: hypromellose 1.0 mg, lactose monohydrate 133,50 mg, eoscarmellose sodium 3.0 mg, magnesium stearate 1.5 mg . The composition of capsules of gelatinous fresh size 4: sodium lauryl sulfate 0.08%, water 14.50%, titanium dioxide (E171) 18%, gelatin 83.31%. Each capsule 5.0 mg contains: Active ingredient: tacrolimus 5.0 mg. Additives: hypromellose 5.0 mg. lactose monohydrate 121.5 mg, croscarmellose sodium 7.0 mg, magnesium stearate 1.5 mg. The composition of capsules of gelatinous solid size No. 4: sodium lauryl sulfate 0.08%, water 14.50%, titanium dioxide (E171) 5350%, iron dye oxide red (E172) 0.9600%, ferric oxide red oxide (E172) 0.0240% , gelatin 81.90%. The composition of the red ink used to inscribe the capsule: shellac 10-14%, ethanol 13-17%, isopropanol 18-24%, butanol 6-11%, propylene glycol 5%, sodium hydroxide 0.05-0, 1%, titanium dioxide (E171) 2-5%, povidone 8-12%, dye red charming (E129) 19-24%. The composition of the white ink used to inscribe the capsule: shellac 19-25%, ethanol 18-24%, isopropanol 0.5-4%, butanol 0.5-6%,propylene glycol 1.5-4%, ammonia solution concentrated 1-2%, water 12-16%, potassium hydroxide 0.02-0.25%, titanium dioxide (E171) 28-34%.

Description:Capsules 0.5 mg
Hard gelatin capsules in the size "№4" of yellow color with red marking "RDY 525" on the body and "0.5MG" on the lid. The contents of the capsule are white or almost white powder.

Capsules 1 mg
Hard gelatin capsules with a size of "4" white with red marking "RDY 526" on the body and "1MS" on the lid. The contents of the capsule are white or almost white powder.

Capsules 5 mg
Hard gelatin capsules in the size "№ 4" brownish-pink color with white marking "RDY 527" on the body and "5MG" on the lid. The contents of the capsule are white or almost white powder.

Pharmacotherapeutic group:immunosuppressive agent - calcineurin. Inhibitor.

Pharmacodynamics:Tacrolimus binds to the cytosolic protein (FKBP12), which is responsible for intracellular cumulation of the drug. The complex FKVP12-tacrolimus specifically and competitively interacts with calcineurin, inhibits it, which leads to a dependent dependence of T-cell signaling, transduction and prevention of transcription of a discrete group of lymphokine genes.Suppresses the formation of cytotoxic lymphocytes, which are mainly responsible for graft rejection, reduces T cell activation, T-helper dependent B-cell proliferation, and the formation of lymphokines (interleukin-2, and 3 and gamma-interferon), expression of the receptor interleukin-2.

Pharmacokinetics:

Absorption

Tapholimus is absorbed from the gastrointestinal tract; the main place of absorption is the upper part of the gastrointestinal tract.

The concentration of tacrolimus in the blood reaches a peak (C max) after about 1-3 hours. In some patients, the drug is continuously absorbed for a long period of time, reaching a relatively flat absorption profile. The average values of the absorption parameters are as follows:

Population	Dosage (mg / kg / day)	FROM max (ng / ml)	TСmах (hour)	Bioavailability (%)
An adult liver transplant (equilibrium concentration)	0,30	74,1	3.0	21,8 (±6,3)
Transplant liver of the child (equilibrium concentration)	0,30	37,0 (± 26,5)	2,1 (±1,3)	25 (± 20)
Kidney transplant "tall man equilibrium concentration)	0,30	44,3 (±21.9)	1,5	20,1 (±11,0)

After oral administration (0.30 mg / kg / day) of the drug to patients with liver transplant, equilibrium tacrolimus concentrations were achieved in most patients for 3 days.

In patients with a liver transplant in a stable state, the bioavailability of tacrolimus was reduced by oral administration of the drug after a meal with a moderate fat content. A decrease in the area of iodine of the pharmacokinetic curve "concentration-time" (AUC) by 27%, the maximum concentration (Stach) at 50% and an increase in the time to reach the maximum concentration (Tonakh) by 173% in whole blood. With simultaneous application of the drug with food, the rate and degree of absorption of tacrolimus decreased.

In patients with kidney transplant who took tacrolimus immediately after a generous breakfast, the effect on bioavailability was less pronounced. Reduced AUC by 2-12% and Stach by 15-38%, as well as an increase in Tmax by 38-80% in whole blood.

The division of bile does not affect the absorption of tacrolimus.

There is a strong correlation between AUC and the minimum levels of the drug in whole blood when the equilibrium state is reached, and therefore monitoring of mycotic levels of the drug in whole blood can serve to adequately assess the systemic effect of the drug.

Distribution

The distribution of tacrolimus after intravenous administration of the drug to humans is biphasic.

In the systemic circulation tacrolimus largely associated with erythrocytes. The ratio of the distribution in the whole blood of plasma concentrations is approximately 20: 1. In plasma, the drug largely (> 98.8%) binds to proteins, mainly with serum albumin and w-acid glycoirotein. Tacrolimus has a large volume of distribution in the body. The equilibrium volume of distribution based on plasma concentrations is approximately 1300 liters (healthy volunteers). The corresponding indicator on the basis of whole blood in: the 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 the concentrations of the drug in the blood, was 2.25 l / h. In adult patients with a liver and kidney transplant, the values of this parameter were 4.1 l / h and 6.7 l / h, respectively. In children (a liver transplant, the value of total clearance is approximately 2 times higher than in adult patients with a liver transplant.The hemispherical period (T1/2) Tacrolimus I is long-lived and variable. In healthy volunteers, the mean T1/2 of the whole is about 43 hours. In adult patients and children with graft transplant, the period of nodulation is, on average, 11.7 hours and 12.4 hours, respectively, compared to 15.6 hours in adult patients with a kidney transplant.

Metabolism

Using in vitro eight metabolites were identified, among which only one metabolite possesses significant immunosuppressive activity.

Tacrolimus is largely metabolized by hepatic microsomal tsntohromom P-4503A4, isoenzyme (CYP3A4).

Excretion

After oral administration ¹⁴C-labeled tacrolimus, most of the radioactivity was found in feces, about 2% in urine, while about 1% of tacrolimus was determined unchanged. Consequently, tacrolimus before elimination almost completely metabolized, the main way of elimination was bile.

Indications:Prevention and treatment of the rejection reaction of liver, kidney and heart allograft, including those resistant to standard regimens of immunosuppressive therapy.

Contraindications:

Increased individual sensitivity to tacrolimus (or other macrolides), any of the components of the drug.

Deficiency of lactase, lactose intolerance, glucose-galactose malabsorption.

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 so women receiving this drug should cancel breast-feeding.

Dosing and Administration:Therapy with the preparation of Redinesp® requires careful monitoring by the personnel having the appropriate qualifications and having the necessary equipment at their disposal. It is only doctors who have experience in carrying out shunosuppressive therapy in patients with transplanted organs to prescribe the preparation of Redinsp® or to make changes in the noise-suppressive therapy.

The uncontrolled transfer of patients from one drug tacrolimus to another (including ehod from conventional capsules to prolonged capsules) is unsafe. This can lead to rejection of the transplant or an increase in the incidence of side effects, including hypo- or hyperimmunosuppression due to the appearance of clinically significant differences in the exposure of tacrolimus. The patient should take one of the medicinal 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 skip reception capsules of the preparation Redinesp® it is necessary to 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, the preparation of Redinsp® is usually used in combination with other immunosuppressants. The dose may vary depending on the regimen of immunosuppressive therapy. The choice of the dose of the drug Redinesp® 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.

In most cases, the preparation of Redinsp® in capsule form is administered orally; If necessary, the contents of the capsules can be mixed with water and injected through a pasogastric tube. Children under the age of 3 are difficult to swallow a capsule, so after opening the capsule, its contents are mixed with a small amount of water and given to drink to the baby.

The daily dose is divided into 2 doses (morning and evening) in equal doses. Capsules should be taken immediately after they are removed from the blister.

Capsules are washed down with a liquid, preferably water. To achieve maximum absorption of the capsule is recommended to be taken on an empty stomach, 1 hour before or 2-3 hours after eating.

Aboutduration of drug intake.

To prevent rejection of the graft, the state of immunosuppression must be maintained at all times, hence the duration of therapy is not limited.

Transplantliver.

Prevention of rejection - adults.

0,1-0,2 mg / kg / day, the dose should be divided into two doses (for example, in the morning and in the evening). The drug should be started 12 hours after the operation is completed.

Preventing rejection - children.

0.3 mg / kg / day, the dose should be divided into two doses (for example, in the morning and in the evening).

Supportive therapy in 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.Children usually require doses 1.5-2 times higher than doses for adults. Treatment of rejection reaction in adults and children.

It is necessary to use higher doses of tacrolimus in combination with glucocorticosteroids (GCS) and short courses of mono- / ionoclonal antibodies. In case of signs of toxicity, a dose reduction of tacrolimus may be required.

Kidney transplantation.

Prevention of rejection - adults.

Oral therapy with tacrolimus should begin with a dose of 0.2-0.3 mg / kg / day, dividing this dose into 2 divided doses (for example, in the morning and in the evening). The drug should be started approximately 24 hours after the operation is completed.

Prevention of rejection - children.

The initial dose of the drug for oral administration of 0.3 mg / kg / day should be divided into 2 doses (for example, in the morning and in the evening).

Supportive therapy in adults and children.

The dose is usually reduced; in some cases tacrolimus can be used as a basic monotherapy (cancellation of concomitant immuno-suppressive drugs). Improvement of the patient's condition after transplantation can explain the pharmacokinetics of tacrolimus, which may require correction of the dose of the drug. The dose is selected individually, according to the results of the clinical trialThe process of rejection and drug tolerance. If the clinical signs rejections are obvious, it is necessary to consider changing the regime of immunosuserous therapy.

Treatment of rejection reaction in adults and children.

It is necessary to use higher doses of tacrolimus in combination with GCS and short courses of mono- / polyclonal antibodies. In case of signs of toxicity of the mosquito, tacrolimus dose reduction is required.

Heart transplantation.

Prevention of rejection - adults.

Tacrolimus can be used in combination with induction therapy with antibodies (which allows delaying the onset of drug use tacrolimus) or without the appointment of antibodies in clinically stable patients. Following induction by antibodies, oral peritoneal therapy with tacrolimus capsules should begin at a dose of 0.075 mg / kg / day divided into two doses (eg, in the morning and in the evening), within 5 days after surgery, once the patient's clinical condition is stabilized. If the patient's condition does not allow taking the drug inside, intravenous infusion should be started at a dose of 0.01-0.02 mg / kg / day for 24 hours.There is an alternative approach in which oral administration of tacrolimus begins within 12 hours after transplantation. This approach is intended for patients without tri-signs of impaired function of internal organs (eg, kidneys). In this case tacrolimus in an initial dose of 2-4 mg / day is combined with the drug mycophenolate yuphetil and GCS or sirolimus and GCS.

Prevention of rejection - children.

After heart transplantation in children, primary immunosuppression with the drug tacrolimus can be carried out both in combination with induction by antibodies, and independently. In those cases when the induction by antibodies ns is carried out and tacrolimus is administered intravenously, the recommended initial dose is 0.03-0.05 mg / kg / day in a continuous 24-hour infusion until the concentration of tacrolimus in the blood of 15-25 IU / ml is reached, and the patient should be transferred at the earliest opportunity for oral administration of the drug. The initial oral dose should be 0.3 mg / kg / day and be administered 8-12 hours after discontinuation of intravenous infusion. Following the induction of antibodies, oral administration of capsrols of tacrolimus should begin with a dose of 0.1-0.3 mg / kg / day, divided into two doses (for example, in the morning and in the evening).

Supportive therapy - adults and children.

In the course of maintenance therapy, the dose of tacrolimus usually decreases. Improvement of the patient's condition after transplantation can change the pharmacokinetics of tacrolimus, and there is a need for correction of the dose of the drug.

Treatment of rejection reaction - adults and children.

To treat episodes of rejection, higher doses of tacrolimus should be used in combination with complementary therapy with GCS and short courses of mono- / polyclonal antibodies.

When transferring patients to tacrolimus capsules, the initial daily dose (0.15 mg / kg / day for adults and 0.2-0.3 mg / kg / day for children) should be divided into two doses (for example, in the morning and in the evening).

Adjusting the dose of the drug in specific patient populations

Patients with hepatic insufficiency.

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

Patients with renal insufficiency.

Since the pharmacokinetics of tacrolimus does not change with the function of the kidneys, there is no need to adjust the dose of the drug. However, in connection with the presence in the tacrolimus of perfrotoxicit is recommended that the kidney function is carefully monitored (including serum creatinine concentration, creatinine clearance, and diuresis level).

Children.

To achieve similar concentrations of the drug in the blood, children usually require doses that are 1.5-2 times higher than doses for adults.

Elderly patients.

Currently, there is no evidence of the need to adjust the dose of the drug for elderly patients.

Translation from therapy with cyclosporine.

The combined use of cyclosporine and tacrolimus may increase the half-life of cyclosporin and increase toxic effects. Therefore, caution should be exercised when transferring patients from cyclosporine to topolimus therapy. Treatment with tacrolimus should begin after an assessment of the concentrations of cyclosporine in the patient's blood and the clinical state of the patient. The use of the drug should be postponed if there is an elevated level of cyclosporine in the patient's blood. On practice tacrolimus is appointed 12-24 hours after cessation of cyclosporine. After transferring the patient to tacrolimus it is necessary to continue monitoring the levels of cyclosporine in the patient's blood in connection with the possibility of violations in the clearance of cyclosporine.

Recommendations for achieving the required level of drug concentration in whole blood.

The choice of tacrolimus dose is based on the clinical assessment of rejection and tolerability of the drug in each individual patient. In order to optimize dosing, the determination of tacrolimus concentration in whole blood with pomA number of immunological methods, including semi-automatic enzyme-linked immunosorbent assay (MICA). A comparison of the results of monitoring the concentration of tacrolimus in the blood published in the literature with monitoring results in a separate clinic should be carried out taking into account the method used to determine the concentration of tacrolimus in the blood.

In the early period after the operation, the minimum levels of tacrolimus in the whole blood should be monitored. When administered orally to determine the minimum levels of the drug in the blood, it is necessary to obtain blood samples 12 hours after taking the drug, immediately before the next dose. The frequency of monitoring the level of the drug in the blood should depend on the clinical needs, as tacrolimus is a preparation with a low level of clearance, adjustment of the dosing regimen can take several days until the moment when changes in the level of the drug in the blood become obvious. The minimum levels of the drug in the blood should be monitored approximately 2 times per week during the early post-transplant period and then periodically during the maintenance ttape. It is also necessary to monitor the minimum levels of tacrolimus in the blood and the green of the dose change of the drug, changes in the immunosuppressive regimen, or after joint application with drugs that may affect the concentration of tg of the rabbit in whole blood.

The results of the analysis of clinical studies suggest that it is possible to successfully treat most patients if the minimum level of tacrolimus in the blood does not exceed 20 ng / ml.

In clinical practice, during the early period after transplantation miThe lowest level of the drug in whole blood usually ranged from 5-20 mg ml in liver transplant recipients and 10-20 ng / ml in patients with grafts in the pen and heart.Later, during maintenance therapy after liver, kidney and heart transplantation, tacrolimus concentration in the blood usually varies from 5 to 15 ng / ml.

Side effects:

Very frequent (> 1/10 appointments); frequent (1/10 - 1/100 appointments); infrequent (1/100 - 1/1000 appointments); rare (1/1000 - 1/10 000 appointments); very rare (<1/10 000 appointments); the frequency is unknown (according to available data, it is possible to establish the frequency of occurrence of ns).

Heart Disease: often - ischemic coronary disorders, tachycardia; infrequently - ventricular arrhythmias and cardiac arrest, heart failure, cardiomyopathies, ventricular hypertrophy, supraventricular arrhythmias, palpitations, abnormal ECG parameters, disturbances in rhythm and heart rate and heart rate; rarely - pericardial effusion; very rarely - abnormal indicators of the echocardiogram.

Vascular disorders: very often - arterial hypertension; often - bleeding, thromboembolic and ischemic complications, violation of peripheral blood circulation, arterial hypotension; infrequently - a heart attack, a thrombosis of deep veins of extremities, a shock.

Disorders from the gastrointestinal tract: very often - diarrhea, nausea; often - symptoms of violations of the gastrointestinal tract, vomiting, gastrointestinal and abdominal pain, inflammatory diseases of the gastrointestinal tract, gastrointestinal bleeding, gastrointestinal ulcers and perforations, ascites, stomatitis and ulceration of the oral mucosa, constipation , indigestion. flatulence, feelings of bloating and swelling in the abdomen, loose stools; infrequently - acute and chronic pancreatitis, peritonitis, increased activity of amylase in the blood, paralytic intestinal obstruction (paralytic ileus), gastroesophageal reflux disease, violation of the evacuation function of the stomach; rarely pancreatic pseudocysts, subillus.

Violations from the blood and lymphatic system: often - anemia, leukopenia, thrombocytopenia, leukocytosis, a decrease or increase in hemoglobin and / or hematocrit; infrequently - coagulopathy, clotting and bleeding disorders, insufficiency of the hematopoietic system, deviations in coagulogram indices, shnitsitopenia, neutropenia; rarely thrombotic thrombocytopenic purpura,gnoprothrombinemia; frequency unknown: partial red cell aplasia, agranulocytosis, hemolytic anemia.

Disorders from the kidneys and urinary tract: very often - impaired renal function; often - renal failure, acute renal failure, olguria, acute tubular necrosis, toxic nephropathy, urinary syndrome, disorders of the bladder and urethra; infrequently - anuria, hemolytic mycotic syndrome; rarely - nephropathy, hemorrhagic cystitis. metabolism and nutrition disorders: very often - hyperglycemia, diabetes, hyperkalemia; often - hypomagnesemia, gynophosphatemia, hypokalemia, hypocalcemia, hyponatremia. hypervolemia, hyperuricemia. decreased appetite, anorexia. metabolic acidosis, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia. electrolyte disturbances; infrequently - dehydration, hypoproteinemia, hyperphosphaemia, hypoglycemia.

Disturbances from the musculoskeletal and connective tissue: often - arthralgia, muscle cramps, pain in the limbs, back pain; infrequently - articular disorders.

Disorders from the endocrine system: rarely: hirsutism.

Impaired nervous system: very often - a tremor, a headache; often - convulsive syndrome of various genesis, impaired consciousness, paresthesia and dysesthesia, peripheral neuropathies, dizziness, violation of writing, nervous system disorders; infrequently - coma, hemorrhages in the central nervous system and disorders of cerebral circulation, paralysis and paresis, encephalopathy, speech disorders and with rticulation, amnesia; rarely - increased muscle tone; very rarely - myasthenia gravis. Disorders from the side of the organ of vision: often: impaired vision, blurred vision, photophobia; infrequently: cataract; rarely: blindness.

Hearing disorders and labyrinthine disturbances: often: tinnitus; infrequently: hearing loss; rarely: sensorineal deafness; very rarely: hearing loss. Disorders of the psyche: very often insomnia; often - anxiety, confusion and disorientation, depression, depressed mood, emotional disorders, nightmares, hallucinations, mental disorders; infrequently - psychotic disorders.

Disturbances from the respiratory system, chest and mediastinal organs: often - dyspnea, pulmonary parenchymal disorders, pleural effusion, pleurisy, frogritis, cough, nasal congestion, rhinitis; infrequent - respiratory failure, respiratory tract disorders, asthma; rarely acute respiratory distress syndrome.

Infringements from skin and subcutaneous tissues: often - itching, rashes, alopecia, acne, hyperhidrosis; infrequently - dermatitis, photosensitivity; rarely - toxic epidermal necrolysis (Lyell's syndrome); very rarely - Stevens-Johnson syndrome.

Disorders from the liver and bile ducts: often - a change in the activity of liver enzymes, violations of liver function, cholestasis and jaundice, damage to liver cells and hepatitis, cholangitis; rarely - hepatic artery thrombosis, obliterating hepatic vein endophlebitis; very rarely - liver failure, stenosis of the bile duct.

Violations of the genitals and mammary glands: not often - dysmenorrhea and uterine bleeding.

Immune system disorders: allergic and anaphylactic reactions.

Benign, Malignant and unidentified neoplasms (including cysts and polyps): patients receiving immunosuppressive therapy have a higher risk of malignant tumors. When tacrolimus was used, both benign and malignant neoplasms appeared, including the Epstein-Barr virus (EBV) - Associated lymphoproliferative diseases and malignant neoplasms of the skin. Infectious and parasitic diseases: against the background of tacrolimus therapy, as well as other immunosuppressants, the risk of local and generalized infectious diseases (viral, bacterial, fungal, protozoal) increases. The course of previously diagnosed infectious diseases may worsen. Cases of nephropathy associated with BV virus, as well as progressive multifocal leukoencephalopathy (LMW) associated with JC-virus, were observed against the background of immunosuppressive therapy, including tacrolimus therapy. Injuries, 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.Some of these cases have been reported to be associated with transplant rejection (it is not possible to estimate the rate of freefall from available data).

General disorders and disorders at the site of administration: often - asthenia, febrile conditions, swelling, pain and discomfort, increased alkaline phosphatase activity in the blood, weight gain, impaired body temperature perception; infrequently - multi-organ failure, influenza-like syndrome, impaired perception of the temperature of the environment, a feeling of squeezing in the chest, a sense of anxiety, worsening of well-being, increased lactate dehydrogenase 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.

When administered orally, the incidence of side effects is lower than with intravenous administration.

Overdose:

Symptoms: tremor, headache, nausea, vomiting, infection, urticaria, lethargy, increased blood urea nitrogen concentration and hypercreatininaemia, increased activity of alanine aminotransferase.

Treatment: symptomatic; gastric lavage and / or intake of adsorbents (Activated carbon). There is no specific antidote. Due to the high molecular weight, poor solubility in water and high coupling with erythrocytes l plasma proteins, it is expected that dialysis is not effective. In individual patients with a very high concentration of the drug in the blood plasma, hemofiltration and diafiltration were effective, reducing toxic drug concentrations. The clinical experience of overdose management is limited.

Interaction:

Metabolic interactions

Tacrolimus, located in the systemic blood stream, is metabolized in hepatic cytochrome CYP3A4. There is also evidence of gastroplastic metabolism of tacrolimus in CYP3A4 in the wall of the intestine. Simultaneous five substances inhibiting or inducing CYP3A4, can affect the metabolism of tacrolimus, and, accordingly, reduce or increase the concentration of tacrolimus in the blood plasma.

To maintain adequate and constant exposure of tacrolimus while simultaneously use with drugs that can change activity CYP3A4 or to have a different effect on the pharmacokinetics of tacrolimus, it is recommended to control the concentration of tacrolimus in the blood and. if necessary, adjust the dose or cancel the drug. Also, attention should be paid to the kidney function and possible to exact effects.

Inhibitors of Metabolism

Increased tacrolimus levels in the blood have been demonstrated clinically for the following substances:

- significant interactions were observed with antifungal agents, such as ketoconazole, fluconazole, itraconazole and voriconazole, antibiotics of the macrolide group (for example, erythromycin), HIV protease inhibitors (eg, ritonavir. nelfinavir, saquinavir) or hepatitis C protease inhibitors (telaprevir, boceprevir). The simultaneous use of these drugs may require a reduction in the dose of tacrolimus in almost all patients.

- weaker interactions were observed with the following drugs: clotrimazole, clarithromycin, josamycin, nifedipine, nicardipine, diltiazem, verapamil, amiodarone, danazol, ethinyl estradiol, omeprazole and pefazodone. based on research results in vitro it was demonstrated that the following drugs are the only inhibitors of tacrolimus metabolism: bromocriptine, cortisone, dapsone, ergotamine, gestodene, lidocaine, mephenytoin, miconazole, midazolam, nilvadipine, norethisterone, quinidium, tamoxifen, troleandomycin.

It is noted that grapefruit juice increases the level of tacrolimus in the blood, so joint use should be avoided.

Lanosoprazole and ciclosporin can potentially inhibit CYP3A4- mediated metabolism of tacrolimus and thereby increase the concentration of tacrolimus in the blood.

Inductors of metabolism

Strong interactions were observed with the following drugs: rifampicin, phenytoin, St. John's wort. Joint use with these drugs may require an increase in the dose of tacrolimus in almost all patients.

Clinically significant interactions were also observed with phenobarbital. Studies in animals have shown that tacrolimus can reduce clearance and increase the half-life of phenobarbital and phenazone.

A decrease in the level of tacrolimus in the blood was observed with the use of maintenance doses of GCS.

It was shown that high doses of prednisolone or methylprisnisolone, prescribed for the treatment of acute rejection, both increase and lower the level of tacrolimus in the blood.

Such drugs as car carbamazepine, metamizole and isoniazid also reduce thetacrolimus in the blood.

Effect of tacrolimus on the metabolism of other drugs Tacrolimus is an inhibitor CYP3A4, therefore, its simultaneous use with drugs that are metabolized in CYP3A4, can affect the metabolism of such drugs.

It was shown that the half-life of cyclosporin increased with simultaneous application with tacrolimus. In addition, synergistic / additive nephrotoxic effects may develop. For these reasons, combined use of cyclosporin and tacrolimus is not recommended for the administration of tacrolimus to patients who previously received ciclosporin. It is noted that taking tacrolimus helps to increase the level of phenytoin in the blood.

As tacrolimus can reduce the clearance of steroid contraceptives and lead to an increase in the exposure of hormones, special attention should be paid to the choice of Contraception.

At present, there is insufficient information on the interaction between tacrolimus and tatins. The available data indicate that the pharmacokinetics of the statins are different when applied simultaneously with tacrolimus.

Other interactions

The combined use of tacrolimus with drugs that exhibit nsphrotoxic and g-peyrotoxic effects may increase the level of toxicity (eg, aminoglycosides, gyrase inhibitors, vancomycin, sulfamethoxazole + trimethoprim, NSAIDs, ganciclovir or acyclovir).

Increased nephrotoxicity was observed after taking amphotericin B and ibuprofen in combination with tacrolimus.

Since treatment with tacrolimus may be accompanied by the development of hyperkalaemia, or may increase the rape of existing hyperkalemia, excessive intake of potassium or potassium-sparing diuretics should be avoided (for example, amiloride, triamterene or spironolactone).

Immunosuppressants can change the body's response to vaccination: vaccination during treatment with tacrolimus may be less effective. The use of live attenuated vaccines should be avoided.

Binding to proteins

Tacrolimus largely binds to blood plasma proteins. Consideration should be given to possible interactions with other drugs that have a high affinity for blood proteins (eg, IPVP, oral anticoagulants or oral antidiabetic drugs).

Special instructions:

In the initial post-transplant period, the following parameters should be regularly monitored: blood pressure, ECG, neurological status and vision state, fasting blood glucose concentration, electrolyte concentrations (especially potassium), liver and kidney function parameters, clinical blood analysis parameters, coagulogram and protein concentration in the blood plasma. When detecting clinically significant abnormalities, correction of immunosuppressive therapy is necessary. In case of simultaneous use with drugs that are inhibitors of 3YP3A4 (for example, telaprevir, boceprevir, ritonavir, ketoconazole, voricoazole, detraconazole, teligromycin or clarithromycin) or inductors CYP3A4 (for example, rifampicin, rifabugia), 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 remedies with tacrolimus treatment should be avoided because of the risk of their possible interaction, which leads to a decrease in blood tacrolimus concentration and a decrease in its clinical effect. Since the concentration of tacrolimus in the blood can change significantly when diarrhea occurs, additional monitoring of the tacrolimus concentration is necessary in this case.

Simultaneous use of cyclosporine and tacrolimus should be avoided, and caution should be exercised when treating tacrolimus patients who previously received ciclosporin (see the section on "Transfer of Cyclosporine Therapy").

In rare cases, ventricular hypertrophy or septatic septum hypertrophy reported as cardiomyopathy was observed, most cases were reversible and were observed primarily in children with a significant excess of the maximum recommended level of tacrolimus concentration in the blood. Other risk factors for these clinical conditions, including pre-existing heart disease, use of GCS, hypertension, renal or hepatic dysfunction, infections, gynervollemia, and edema, have been identified.Therefore, high-risk patients, especially young children and those undergoing intensive immunosuppression, should undergo examinations such as echocardiography and ECG before and after transplantation (for example, 3 months before and then 9-12 months after) . When identifying abnormalities, consideration should be given to reducing the dose of tacrolimus or substituting it for another immunosuppressive therapy. The application of tacrolimus may lead to lengthening of the interval QT. at the same time there is no data for the development of tachycardia such as "pirouette". Caution should be exercised in patients with diagnosed or suspected congenital syndrome of elongated QT.

In patients who received tacrolimus, possibly the development of post-transplant lymphoproliferative diseases (PTLZ) associated with the Epstein-Barr virus. With the simultaneous use of tacrolimus with antilymphocytic antibodies, the risk of PTLZ increases. There is also evidence of an increased risk of PTFE in patients with the identified carrier of the Epstein-Barr virus capsid antigen. Virus - Epstein-Barr - negative children, children of younger age (<2 years) have an increased risk of developing lymphoproliferative diseases.Thus, in this group of patients, a serological study of the presence of the Epstein-Barr virus capsid antigen should be performed; Antigenic status should be established before treatment with tacrolimus. During treatment, it is recommended careful monitoring of the Epstein-Barr virus. Positive PCR for the pstein-Barr virus can persist for several months and in itself is not evidence of PTLZ or lymphoma.

In patients who received tacrolimus, there was a development of the syndrome of posterior reversible ectsefalopathy (ZOE). If patients taking tacrolimus, egmptoms that indicate an SOE syndrome, such as headache, changes in the state of the illness, convulsions and visual impairment, should be performed by radiological examinations (eg, MRI). If SOE syndrome is confirmed, blood pressure control is recommended and immediate preapplication of tacrolimus. Most patients completely are restored after appropriate measures.

Have patients receiving immunosuppressive therapy, including tacrolimus, increased risk of opportunistic infections (caused by bacteria, fungi, viruses, protozoa). Among these infections, there is nephropathy associated with BV virus, and associated with JC-virus progressive multifocal leukoencephalopathy (PML). 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.

Cases of partial red cell aplasia of the bone marrow (PCCA) were noted in patients taking tacrolimus. In all cases, the presence of such risk factors for PKA as an infection caused by parvovirus B19 has been reported, contributing to pcc disease or simultaneous administration of drugs associated with PKA.

Due to the potential risk of developing malignant skin diseases during treatment, exposure to sunlight and UV radiation should be limited, protecting the skin with clothing and using creams with a high protective factor.

As with other immunosuppressive drugs, the likelihood of developing a secondary cancer is unknown.

Gacrolimus is not compatible with polyvinyl chloride (PVC). Tubes, syringes, lasagne probes and other equipment used in the preparation and administration of the suspension from the contents of the capsules 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 abnormalities should not drive a car or work with them. Ego exposure can be exacerbated by simultaneous administration of pacrolimus with alcohol.

During the treatment period, the patient should refrain from engaging in potentially dangerous activities requiring increased attention and speed of psychomotor reactions (including driving).

Form release / dosage:Capsules 0.5 mg, 1 mg, 5 mg.

Packaging:Capsules 0.5 mg and 1 mg: 10 capsules in a foil / aluminum foil blister foil / aluminum foil, laminated paper, or K) capsules in a blister (PA / A1 / PE with desiccant / HDPE) foil / ( PE / A1) of the foil. For 5 or K) blisters in a pack kagonnuyu together with instructions for use.
Capsules of 5 mg: 10 capsules per blister (PA / A1 / PVC) foil / aluminum foil, laminated paper, or 10 capsules per blister (PA / A1 / PE desiccant / HDPE) foil / (PE / A1) foil. For 5 blisters in a pack of cardboard along with instructions for use.

Storage conditions:At a temperature of no higher than 25 ° C.
Keep out of the reach of children!

Shelf life:

2 years. Do not use after the expiration date indicated on the packaging.

Terms of leave from pharmacies:On prescription

Registration number:LP-003077

Date of registration:06.07.2015

The owner of the registration certificate:Dr. Reddy's Laboratories Ltd.Dr. Reddy's Laboratories Ltd. India

Manufacturer: & nbsp

DR. REDDY`S LABORATORIES, LTD. India

Representation: & nbspDr. Reddy`c Laboratoris Ltd.Dr. Reddy`c Laboratoris Ltd.

Information update date: & nbsp31.08.2015

Illustrated instructions

Instructions

Redesp (Redinesp)