Capsules of prolonged action hard gelatinous, size 5, on the pale yellow cap of the capsule there is a red inscription "0.5 mg", on the orange capsule case - "firm logo 647"; the contents of the capsules are white powder.
1 caps.
tacrolimus monohydrate 0.51 mg,
which corresponds to the content of tacrolimus 0.5 mg
Excipients: hypromellose 0.15 mg, ethyl cellulose 0.15 mg, lactose monohydrate 53.64 mg, magnesium stearate 0.55 mg.
The composition of the capsule shell: titanium dioxide (E171) - 0.366 mg, iron dye oxide yellow (E172) - 0.128 mg, iron oxide red (E172) 0.01 mg, gelatin - 27.496 mg, sodium lauryl sulfate - traces.
Ink composition (Opacode S-1-15083): pharmaceutical glaze 45% (shellac solution in ethanol) - 60.7%, lecithin (soybean) 0.48%, simethicone 0.01%, iron dye red oxide (E172) 20%, giprolose - 0.3%.
10 pieces. - blisters (5) - aluminum bags (1) - packs of cardboard.
Capsules of prolonged action hard gelatinous, size 4, on the white cap of the capsule there is a red inscription "1 mg", on the orange capsule case - "677 company logo"; the contents of the capsules are white powder.
1 caps.
tacrolimus monohydrate 1.02 mg,
which corresponds to the content of tacrolimus 1 mg
Excipients: hypromellose 0.3 mg, ethyl cellulose 0.3 mg, lactose monohydrate 107.28 mg, magnesium stearate 1.1 mg.
The composition of the capsule shell: titanium dioxide (E171) - 0.716 mg, iron oxide oxide yellow (E172) 0.156 mg, iron oxide red (E172) 0.014 mg, gelatin 39.114 mg, sodium lauryl sulfate traces.
Ink composition (Opacode S-1-15083): pharmaceutical glaze 45% (shellac solution in ethanol) - 60.7%, lecithin (soybean) 0.48%, simethicone 0.01%, iron dye red oxide (E172) 20%, giprolose - 0.3%.
10 pieces. - blisters (5) - aluminum bags (1) - packs of cardboard.
Capsules of prolonged action hard gelatinous, size No. 0, red inscription "5 mg" on the gray-red cap of the capsule, on the orange capsule case - "687 firm logo"; the contents of the capsules are white powder.
1 caps.
tacrolimus monohydrate 5.1 mg,
which corresponds to the content of tacrolimus 5 mg
Excipients: hypromellose - 1.5 mg, ethyl cellulose - 1.5 mg, lactose monohydrate - 536.4 mg, magnesium stearate - 5.5 mg.
The composition of the shell of the capsule: titanium dioxide (E171) - 1.308 mg, iron oxide oxide yellow (E172) - 0.39 mg, iron oxide red (E172) - 0.104 mg, gelatin 98.198 mg, sodium lauryl sulfate - traces.
Ink composition (Opacode S-1-15083): pharmaceutical glaze 45% (shellac solution in ethanol) - 60.7%, lecithin (soybean) 0.48%, simethicone 0.01%, iron dye red oxide (E172) 20%, giprolose - 0.3%.
10 pieces. - blisters (5) - aluminum bags (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2017.
PHARMACHOLOGIC EFFECT
Immunosuppressant. 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.
PHARMACOKINETICS
Suction
It has been established that in the human body tacrolimus is rapidly absorbed from the digestive tract. Capsules of prolonged action - a dosage form, providing a long-term absorption of tacrolimus in the digestive tract. The average time to reach C max is about 2 hours. The absorption of tacrolimus is variable (the absorption variability 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. After attaining C ss tacrolimus, Advagraf received a high correlation between AUC and minimal (C 0 ) tacrolimus concentrations in the blood. Therefore, monitoring the minimum (C 0 ) concentrations of tacrolimus in the blood allows you to judge the systemic exposure of the drug.
Distribution
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. The stationary V d 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.
Metabolism
Tacrolimus is actively metabolized in the liver, mainly by means 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 the drug is practically independent of metabolites.
Excretion
Tacrolimus is a substance with 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. SCS 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.
After intravenous administration and oral administration of 14 C-labeled tacrolimus, the major portion of radioactivity was found in feces. Approximately 2% of radioactivity was recorded in urine. In urine and feces, about 1% of tacrolimus was determined unchanged. Consequently, tacrolimus was almost completely metabolized before excretion.The main way of elimination was bile.
INDICATIONS
- prevention and treatment of liver allograft rejection, kidney in adult patients;
- treatment of allograft rejection, resistant to standard regimens of immunosuppressive therapy in adult patients.
DOSING MODE
Advagraf В® is the oral form of tacrolimus for taking 1 time / day. Therapy with the drug Advagraf В® requires careful monitoring by personnel with the appropriate qualifications and having the necessary equipment at their disposal. This drug can be prescribed only by physicians with experience of carrying out immunosuppressive therapy in patients with transplanted organs.
The uncontrolled transfer of patients from one drug tacrolimus to another (including the transition from conventional capsules to prolonged capsules) is unsafe. This can lead to rejection of the transplant or an increased 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 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.
The initial doses presented below should only be considered as recommendations. In the initial postoperative period, AdvagrafВ® 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 AdvagrafВ® should be based, first of all, on the clinical assessment of the risk of rejection and individual drug tolerance, as well as on the monitoring of tacrolimus blood levels (see section "Recommendations for monitoring therapeutic concentration of tacrolimus 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 stable patients transferred from Prograf В® (twice daily intake) to Advagraf В® (once daily intake), with a total daily dose of 1: 1 (mg: mg), systemic exposure of tacrolimus (AUC 0-24 ) with Advagraf В®was approximately 10% less than Prograf В® . The relationship between the minimum levels of tacrolimus (C 24 ) and the system exposure of the drug AdvagrafВ® was the same as when using Prograf В® . When converting from PrografВ® to AdvagrafВ®, the minimum levels of tacrolimus should be measured both before conversion from one drug to another, and during the next two weeks. In this case, the dose of the preparation of AdvagrafВ® should be adjusted in order to achieve a systemic exposure of tacrolimus similar to the ProgramВ® preparation.
In patients after kidney and liver transplantation de novo AUC 0-24 tacrolimus in the first day of application of the preparation of Advagraf В® was accordingly 30% and 50% lower compared to the equivalent doses of Prograf В® .
By the 4th day the system exposure of tacrolimus, estimated by C 0 , with the use of Prograf В® and the preparation of Advagraf В® in patients after liver and kidney transplantation was the same. In order to ensure an adequate exposure of tacrolimus in the treatment with the drug AdvagrafВ®, regular and careful monitoring of the minimum (C 0 ) concentration of tacrolimus in the blood is recommended during the first two weeks after transplantation. Because tacrolimus is a substance with low clearance, it may take several days to reach equilibrium concentrations after correcting the dose of the drug.
For patients who can not take the medication directly after transplantation, tacrolimus can be administered IV (Prograf В® 5 mg / ml, infusion concentrate) at a dose of about 1/5 of the recommended oral dose for this indication.
Mode of application
The oral daily dose of the drug AdvagrafВ® should be taken in the morning 1 time / day. Receiving capsules prolonged action is carried out immediately after they are removed from the blister. Patients should be warned about the presence of a desiccant in the package (a bag of silica gel), which is not intended for admission. Capsules are recommended to be washed down with liquid (preferably water). To achieve maximum absorption, AdvagrafВ® should be taken on an empty stomach: 1 hour before or 2-3 hours after ingestion. The missed dose should be taken as soon as possible, preferably the same day; Do not take a double dose the next morning.
Duration of the drug
To prevent rejection of the graft, the state of immunosuppression must be maintained constantly; therefore, the duration of therapy is not limited.
Dosing recommendations
Kidney Transplantation
Prevention of graft rejection
Oral therapy with the drug AdvagrafВ® should be started with a daily dose of 0.2-0.3 mg / kg of body weight, 1 time / day in the mornings. The drug should be taken within 24 hours after transplantation.
Liver transplantation
Prevention of graft rejection
Oral therapy with the drug AdvagrafВ® should be started with a daily dose of 0.1-0.2 mg / kg of body weight, 1 time / day (in the morning). The drug should be taken 12-18 hours after transplantation.
Dose adjustment in the post-transplant period
With the passage of time after kidney or liver transplantation, the dose of AdvagrafВ® is usually reduced. In some cases, it is possible to cancel the concomitant immunosuppressants, i.e. transition to monotherapy with the drug Advagraf В® . Improvement of the patient's condition can change the pharmacokinetics of tacrolimus and require additional adjustment of the doses of the preparation of AdvagrafВ®.
Treatment of transplant rejection
For the purpose of arresting transplant rejection, the following approaches are recommended: increasing the dose of tacrolimus, increasing corticosteroid therapy, brief courses of mono- / polyclonal antibody therapy. If signs of toxicity tacrolimus (for example, pronounced undesirable reactions) occur, it may be necessary to reduce the doses of the drug AdvagrafВ®. Information on the transition from cyclosporine to Advagraf В® is contained in the section "Conversion (transition) from cyclosporin to Advagraf В® ".
Kidney and liver transplantation
When switching from other immunosuppressants to AdvagrafВ®, treatment should begin with the initial oral doses described in the sections "Preventing graft rejection" in kidney and liver transplantation.
Heart transplantation
When switching to therapy with the drug Advagraf В® in adult patients , the initial oral daily dose of the drug is 0.15 mg / kg body weight, 1 time / day in the mornings.
Transplantation of other organs
Clinical experience of the use of the drug Advagraf В® for the treatment of patients after a transplantation of the lung, pancreas, intestine is absent. However, tacrolimus (PrografВ®) is used in patients with lung transplants at an initial oral dose of 0.1-0.15 mg / kg / day, after pancreatic transplantation at the initial oral dose of 0.2 mg / kg / day, after intestinal grafting at an initial oral dose of 0.3 mg / kg / day.
Conversion (transition) from cyclosporin to AdvagrafВ®
Care should be taken when switching from cyclosporine to AdvagrafВ®. Treatment with the drug Advagraf В® is recommended to begin after the determination of the concentrations of cyclosporine in the blood and assess the clinical state of the patient. Conversion should be postponed if there is an increased concentration of cyclosporine to the blood. In practice, tacrolimus therapy begins 12-24 hours after discontinuation of cyclosporine. After the transition, it is recommended to monitor the concentration of cyclosporine in the blood, since it is possible to slow the clearance of cyclosporine.
Conversion (transition) from Prograf В® to Advagraf В®
If patients after allotransplant taking Prograf В® 2 times / day should be transferred to the preparation of the preparation of Advagraf В® 1 time / day, the ratio of daily doses during the transition should be 1: 1 (mg: mg). AdvagrafВ® should be taken in the morning. After switching to AdvagrafВ®, it is necessary to monitor the minimum (C 0 ) concentration of tacrolimus in the blood and adjust the dose of the drug to maintain the systemic exposure of tacrolimus at the same level.
Correction of dose in selected categories of patients
Patients with impaired liver function. In patients with severe liver dysfunction to maintain the minimum (C 0 ) concentration of tacrolimus in the blood within the recommended therapeutic range, a dose reduction of the Advagraf В® preparation may be required.
Patients with impaired renal function. Because the kidney function does not affect the pharmacokinetics of tacrolimus, there is no need for dose adjustment. However, due to the nephrotoxic potential of tacrolimus, it is recommended that the renal function be carefully monitored (including determination of serum creatinine, calculation of QC, and control of the amount of urine released).
Race. In patients of the Negroid race, in order to achieve similar minimum (C 0 ) tacrolimus concentrations in the blood, higher doses of the drug may be required than in patients of the Caucasoid race.
Floor. Information that men and women require different doses of the drug to achieve equal minimum (C 0 ) concentrations of tacrolimus in the blood are absent.
Patients of advanced age. Information that elderly patients require special doses of the preparation of Advagraf В® are not available.
Recommendations for monitoring the therapeutic concentration of tacrolimus in the blood
The choice of doses should be based on a clinical assessment of the individual risk of rejection and tolerability of the drug, as well as on the monitoring of the therapeutic level of tacrolimus in the blood.
To select the optimal dose, several methods are used to determine the concentration of tacrolimus in whole blood. Comparison of monitoring results published in the literature with monitoring results in a separate clinic should be performed taking into account the method used to determine the concentration of blood tacrolimus. In current clinical practice, the concentration of tacrolimus in the blood predominantly controlled by immunoassay techniques.
Correlation between the minimum (C 0 , C 24 ) concentrations and systemic exposure (AUC 0-24 ) in the blood tacrolimus when used both drugs, Advagraf В® and Prograf В® , identical.
In the post-transplant period of careful monitoring of the minimum necessary (C 0 , C 24 ) of tacrolimus concentrations in blood. The minimum concentration of the preparation Advagraf В®in the blood should be determined approximately 24 hours after administration of the drug, before taking the next dose. In the first two weeks after transplantation it is recommended to perform more frequent monitoring of the minimum concentration, and then during the maintenance therapy is carried out periodic monitoring. The therapeutic level of tacrolimus in the blood should be carefully monitored after the transition from preparation to Prograf Advagraf В® , at doses of drugs correction, when changes in immunosuppressive therapy regime or concomitant use of drugs that can cause a change in the concentration of tacrolimus in the blood. The frequency of monitoring the concentration of the drug in the blood is determined by clinical necessity. As Advagraf В®- a preparation with low clearance, to achieve equilibrium concentration of tacrolimus in the blood after correcting the drug dose Advagraf В® may require several days.
According to clinical studies, in most cases treated successfully at a therapeutic concentration of tacrolimus in the blood is not higher than 20 ng / ml. In the interpretation of therapeutic concentrations of tacrolimus in the blood of the data must take into account the clinical condition of the patient.
According to available data, the initial post-transplant period in patients after liver transplantation therapeutic concentration in the blood preparation is in the range of 5-20 ng / ml, and after a kidney or heart transplants - 10-20 ng / ml. During maintenance immunosuppressive therapy in patients after liver transplantation, kidney or heart blood concentration of the drug it is generally in the range of 5-15 ng / ml.
SIDE EFFECT
In connection with the features of the underlying disease and many drugs used simultaneously after transplantation, the profile of adverse events immunosuppressants difficult to accurately set.
Many of the adverse reactions presented below, reversible and / or reduced at lower doses. Within each frequency band adverse reactions are presented in order of decreasing seriousness. Adverse reactions classified by organs and systems are listed below in descending order of frequency of occurrence: very common (1/10?), Common (1/100 to <1/10?), Rarely (from 1/1000 to 1 /? 100), rare (by? 1/10 000 to <1/1 000), very rare (<1/10 000), not known (to establish the frequency of which data are insufficient).
Cardio-vascular system:very often - arterial hypertension; often - ischemic coronary disorders, tachycardia, bleeding, thromboembolic and ischemic complications, impaired peripheral circulation, hypotension; infrequently - ventricular arrhythmias and cardiac arrest, heart failure, cardiomyopathy, ventricular hypertrophy, supraventricular arrhythmias, palpitations, abnormal ECG, cardiac arrhythmias, heart rate and heart rate, heart attack, deep vein thrombosis limb, shock; rarely - pericardial effusion; very rarely - an abnormal echocardiogram indexes.
From hemopoiesis system: often - anemia, leukopenia, thrombocytopenia, leukocytosis; rarely - pancytopenia, neutropenia; rarely - thrombotic thrombocytopenic purpura.
From the blood coagulation system: rarely - coagulopathy, deviations in terms of coagulation, rarely - hypoprothrombinemia.
From the nervous system: very often - tremor, headache; often - epileptic seizures, impaired consciousness, paresthesia and dysesthesia, peripheral neuropathy, dizziness, blurred letters; infrequently - coma, bleeding in the central nervous system and cerebrovascular accidents, paralysis and paresis, encephalopathy, speech and articulation disorders, amnesia; rarely - increased muscle tone; very rarely - myasthenia gravis.
Mental disorders:very often - insomnia; often - anxiety, confusion and disorientation, depression, depressed mood, emotional disorder, nightmares, hallucinations, mental disorders; infrequently - psychotic disorders.
From a sight organ: often - blurred vision, photophobia, eye diseases; infrequently - cataracts; rarely - blindness.
On the part of the organ of hearing: often - noise (ringing) in the ears; infrequently - hearing loss; rarely - sensorineural deafness; very rarely - hearing impairment.
The respiratory system:often - shortness of breath, pulmonary parenchymal disorders, pleural effusion, pharyngitis, cough, nasal congestion, rhinitis; infrequently - respiratory failure, disorders of the respiratory tract, asthma; rarely - acute respiratory distress syndrome.
From the digestive system:very often - diarrhea, nausea; often - inflammatory gastrointestinal diseases, gastrointestinal ulceration and perforation, gastrointestinal bleeding, stomatitis and ulceration of the mucous membranes of the oral cavity, ascites, vomiting, gastrointestinal and abdominal pain, dyspepsia, constipation, flatulence, bloating and distension in the abdomen, loose stool, symptoms of disorders of the gastrointestinal tract; infrequently - paralytic ileus (paralytic ileus), peritonitis, acute and chronic pancreatitis, increased amylase levels, gastroesophageal reflux disease, impaired evacuation function of the stomach; rarely - subileus, pancreatic pseudocyst.
Of the liver and biliary tract:frequent - increase in liver enzymes, liver function abnormalities, cholestasis and jaundice, liver damage cells and hepatitis, cholangitis; rare - hepatic artery thrombosis, veno-occlusive disease of the liver; very rare - hepatic failure, stenosis of biliary ducts.
From the urinary system: very often - impairment of renal function; often - kidney failure, acute renal failure, oliguria, acute tubular necrosis, toxic nephropathy, urinary syndrome, disorders of the urinary bladder, and urethra; infrequently - anuria, hemolytic uremic syndrome; very rarely - nephropathy, hemorrhagic cystitis.
Skin and subcutaneous tissue:often - itching, rash, alopecia, acne, rash; infrequently - dermatitis, photosensitivity; rarely - toxic epidermal necrolysis (Lyell's syndrome); very rarely - Stevens-Johnson syndrome.
On the part of the musculoskeletal system: often - arthralgia, muscle cramps, pain in extremity, back pain; infrequently - articular disorders.
From endocrine system: very often - hyperglycemia, diabetes mellitus; rarely - hirsutism.
From a metabolism:very often - hyperkalemia; often - hypomagnesemia, hypophosphatemia, hypokalemia, hypocalcemia, hyponatremia, hypervolemia, hyperuricemia, decrease of appetite, anorexia, metabolic acidosis, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, electrolyte disturbances; infrequently - dehydration, hypoproteinemia, hyperphosphatemia, hypoglycemia.
Infections and infestations:against the backdrop of tacrolimus therapy, as well as other immunosuppressants increases the risk of local and generalized infections (viral, bacterial, fungal, protozoal). May deteriorate over previously diagnosed infectious diseases. Cases of nephropathy associated with BK virus and PML associated with the JC-virus have been observed on the background of immunosuppressive therapy, including therapy with Advagraf В® .
Injury, poisoning, and complications of procedures: often - primary graft dysfunction.
Benign, malignant neoplasms and unidentified:patients receiving immunosuppressive therapy, are at higher risk of cancer. In applying tacrolimus noted occurrence of both benign and malignant tumors, including Epstein-Barr virus - associated lymphoproliferative disorders and skin cancer.
On the part of the reproductive system: rarely - dysmenorrhea, and uterine bleeding. The negative effect of tacrolimus on male fertility, expressed in reducing the number and motility of spermatozoa is established in rats.
Allergic reactions: in patients treated with tacrolimus have been observed allergic and anaphylactic reactions.
General disorders:often - fatigue, fever, swelling, pain and discomfort, increased levels of alkaline phosphatase in the blood, increase in body weight, body temperature perception disturbances; infrequently - multiple organ failure, influenza-like syndrome, disorders of perception of ambient temperature, squeezing sensation in the chest, anxiety, deterioration of health, increasing the level of LDH in the blood, weight loss; rarely - thirst, loss of balance (fall), the feeling of tightness in the chest, difficulty of movement; very rare - increase in adipose tissue mass.
CONTRAINDICATIONS
- hypersensitivity to tacrolimus, other macrolides or any of the excipients.
PREGNANCY AND LACTATION
Results of pre-clinical research and studies conducted in humans have shown that the drug can cross the placenta. There have been reports of premature birth (<37 weeks), as well as cases of hyperkalemia been resolved spontaneously in neonates (8 out of 111 (7.2%) neonates). Because safety of tacrolimus in pregnant women has not been established sufficiently, medication taken during pregnancy only if there is no safer alternative and only in cases where the resulting benefits of treatment justifies the potential risk to the fetus. In order to detect potential adverse events of tacrolimus is recommended to monitor the status of newborns whose mothers took during pregnancy tacrolimus (in particular, pay attention to kidney function).
According to clinical experience, tacrolimus is excreted in breast milk. Because eliminate the adverse effects of tacrolimus in the newborn is not possible for women receiving Advagraf В® , should refrain from breastfeeding.
APPLICATION FOR FUNCTIONS OF THE LIVER
Since renal function did not affect the pharmacokinetics of tacrolimus, no need to adjust the dose. However, in connection with tacrolimus should carefully monitor the nephrotoxic potential of renal function (including the determination of the concentration of serum creatinine, creatinine clearance calculation and control over the amount of urine).
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
In patients with severe hepatic dysfunction to maintain minimum (C 0 ) of tacrolimus concentrations in blood within the therapeutic range recommended may require dose reduction Advagrafa.
APPLICATION IN ELDERLY PATIENTS
Information that elderly patients require a special dose of the drug Advagraf В® , no.
SPECIAL INSTRUCTIONS
Previous treatment for patients non-white race, as well as patients with a high risk of immunological (i.e. when re-transplantation, high titer panel reactive antibodies [PRA]) restricted. Clinical data on the use of the drug Advagraf В® in acute rejection refractory to other immunosuppressive therapy in adult patients, are absent.
Currently, there are no clinical data on the application of the drug Advagraf В® to prevent graft rejection in heart transplant and childhood.
In the initial post-transplant period should be carried out regularly monitors the following parameters: blood pressure, ECG, neurologic status and condition of the level of fasting blood glucose, the concentration of electrolytes (especially potassium), indicators of liver and kidney function, hematology, coagulation, proteinemii level. In the presence of clinically significant changes, a correction of immunosuppressive therapy.
In applying the drug Advagraf В® should be avoided vegetable preparations containing St. John's wort (Hypericum perforatum), and other herbal remedies that can cause a decrease (change) of tacrolimus concentrations in blood and have an adverse effect on the clinical effect of the drug Advagraf В® .
When diarrhea concentration of tacrolimus in the blood can vary considerably; the appearance of diarrhea requires careful monitoring of tacrolimus concentrations in blood.
It should avoid the simultaneous use of cyclosporin and tacrolimus, as well as careful tacrolimus in treating patients who have previously received cyclosporine (cm. "Conversion (transition) with cyclosporine to Advagraf В® ").
Cases of ventricular hypertrophy or hypertrophy of the heart walls, which have been reported as cardiomyopathy is rare, but have been observed in patients receiving PrografВ® , and so there may be in the treatment of drug Advagraf В® . In most cases of myocardial hypertrophy was reversible and occurred at concentrations (P 0) Of tacrolimus in the blood, higher than recommended. Other factors that increase the risk of adverse events include: a prior heart disease, corticosteroid use, hypertension, renal or hepatic dysfunction, infections, hypervolemia, edema. Patients with high risk and receiving intensive immunosuppressive therapy before and after transplantation (3 and 9-12 months) must be done echocardiographic and ECG monitoring. If the detected abnormality, should consider lowering the dose of the drug Advagraf В® or replacement product to another immunosuppressant.
Tacrolimus may cause elongation of interval QT, while cardiac arrhythmias such as "pirouette" (torsades ventricular tachycardia) were observed. In the treatment of patients diagnosed with congenital QT syndrome elongate slot or suspected to have such a state requires special care.
Patients treated with tacrolimus may develop post-transplant lymphoproliferative disease (PTLZ) associated with Epstein-Barr virus. With the simultaneous use of the drug with anti-lymphocyte antibodies increases the risk PTLZ. Also, there is evidence of increasing PTLZ risk patients diagnosed with capsid antigen of Epstein-Barr virus. Therefore, before assigning Advagraf preparation В®in this group of patients should be conducted serological testing for the presence of capsid antigen of Epstein-Barr virus. During treatment, careful monitoring is recommended to Epstein-Barr virus by polymerase chain reaction (PCR). Positive PCR for Epstein-Barr virus may persist for months and is not in itself is a testament to PTLZ or lymphoma.
In patients receiving immunosuppressive therapy, including Advagraf В®Increased risk of opportunistic infections (caused by bacteria, fungi, viruses, protozoa). Among these infections is noted nephropathy associated with BK virus, and JC-associated virus with progressive multifocal leukoencephalopathy (PML). These infections are often associated with a profound suppression of the immune system and can lead to severe or fatal outcomes that need to be considered in the differential diagnosis in patients with signs of renal impairment or
