Prograf 0.5 mg (50 capsules)
- $248.20
STRUCTURE AND PACKAGING:
kaps. 0.5 mg, No. 50
Takrolimus
of 0.5 mg
Other ingredients: a hydroksipropilmetiltsellyuloza, sodium of a kroskarmelloz, lactose, magnesium stearate, the titan dioxide (E171), gelatin, iron oxide yellow, sodium lauryl sulfate, water purified.
No. UA/4994/02/01 from 18.08.2006 till 18.08.2011
kaps. 1 mg, No. 50
Takrolimus
of 1 mg
Other ingredients: a hydroksipropilmetiltsellyuloza, sodium of a kroskarmelloz, lactose, magnesium stearate, the titan dioxide (E171), gelatin, sodium lauryl sulfate, water purified.
No. UA/4994/02/02 from 18.08.2006 till 18.08.2011
kaps. 5 mg, No. 50
Takrolimus
of 5 mg
Other ingredients: a hydroksipropilmetiltsellyuloza, sodium of a kroskarmelloz, lactose, magnesium stearate, the titan dioxide (E171), gelatin, ferrous oxide red, sodium lauryl sulfate, water purified.
No. UA/4994/02/03 from 18.08.2006 till 18.08.2011
konts. baby solution for infection. in/in 5 mg/ml of amp. 1 ml, No. 10
Takrolimus
of 5 mg/ml
Other ingredients: the castor oil hydrogenated by polyoxyethylene 60, anhydrous alcohol.
No. UA/4994/01/01 from 18.08.2006 till 18.08.2011
PHARMACOLOGICAL PROPERTIES: at molecular level the effects of a takrolimus are predetermined by linking with cytosolic protein (FKBP12) which is responsible for intracellular cumulation of drug. The FKBP12-takrolimus complex specifically and competitively communicates with kaltsinevriny and inhibits it that leads to kaltsiyzavisimy inhibition of T-cellular alarm ways of transduction, thus prevents a transcription of discrete group of limfokinny genes. Takrolimus represents highly active immunosuppressive substance, the oppressing forming of cytotoxic lymphocytes which generally are responsible for graft rejection, reduce activation of T-cells, proliferation of V-cells, dependent on T-helperov, and also forming of lymphokines (such as interleukins-2,-3 and γ-interferon), an interleukin-2 receptor expression. Capsules of a takrolimus it is absorbed from a GIT, the main place of absorption is the upper part of a GIT. The maximum concentration in blood plasma (Cmax) of a takrolimus reach peak (Tmax) approximately in 1–3 h. At some patients drug is absorbed throughout the long period, reaching rather uniform profile of absorption. The average value of parameters of absorption is given below:
Population
Dosing (mg/kg/days)
of Cmax (ng/ml)
of Tmax (ch)
Bioavailability (%)
the Transplant of a liver of the adult (equilibrium concentration)
0,30 74,1 3,0 21,8 (±6,3)
Transplant of a liver of the child (equilibrium concentration)
0,30 37,0 (±26,5) 2,1 (±1,3) 25 (±20)
Transplant of a kidney of the adult (equilibrium concentration)
0,30 44,3 (±21,9) 1,5 20,1 (±11,0)
After oral administration (0.3 mg/kg a day) drug at patients with a liver transplant at most of patients the equilibrium concentration were reached for 3 days. At patients with a liver transplant in a stable state the bioavailability of the Pro-count decreased at oral administration of drug after consumption of food with the moderate content of fats. Also decrease in AUC (27%), Cmax (50%) and increase in Tmax (173%) in not divorced blood was noted. At simultaneous use of drug with food the speed and extent of absorption of the Pro-count decreased. Biliation does not influence drug absorption. The considerable correlation between AUC and the minimum levels of drug in not divorced blood at achievement of an equilibrium state in this connection monitoring of the minimum levels of drug in not divorced blood can help with adequate assessment of system influence of drug is noted. The nature of distribution of a takrolimus in/in introductions can be described later as two-phase. In a system blood-groove takrolimus considerably contacts erythrocytes. A ratio not divorced blood / concentration in blood plasma makes 20:1. In blood plasma drug considerably contacts (98.8%) proteins, generally with serumal albumine and a α-1-kisly glycoprotein. Takrolimus widely extends in an organism. The equilibrium volume of distribution (on the basis of concentration in blood plasma) — 1300 l (healthy volunteers). The corresponding indicator on the basis of not divorced blood — 47.6 l. Takrolimus — substance with the low level of clearance. Healthy volunteers have an average value of the general clearance which is estimated on concentration of drug in not divorced blood — 2.25 l/h. Adult patients with a transplant of a liver and kidneys have a value of this parameter — 4.1 and 6.7 l/h respectively. At children with a transplant of a liver of value of the general clearance is twice higher, than at adult patients with a liver transplant. The period semi-removal of a takrolimus is long and changeable. Healthy volunteers have an average value of elimination half-life from not divorced blood — 43 h. Adult patients and children with a transplant of a liver have an elimination half-life on average 11.7 and 12.4 h respectively, in comparison with 15.6 h at adult patients with a kidney transplant. When using in vitro of models 8 metabolites among which only 1 has important immunosuppressive activity are revealed. Takrolimus is considerably metabolized by hepatic microsomal P450 3A4 cytochrome CYP isoenzyme 3A4. After oral introduction of a takrolimus, marked 14C isotope, the majority radioactive mechennogo drug was removed with a stake. About 2% are removed with urine. Less than 1% of not changed takrolimus were noted in urine and Calais, it indicates that it takrolimus is almost completely metabolized before elimination. The main way of elimination — bile.
INDICATIONS: prevention and treatment of rejection of allograft of a liver, kidneys and heart, including resistant to the standard modes of immunosuppressive therapy.
USE: capsules accept inside. Dosing needs to be adjusted depending on specific features of an organism of the patient, considering results of monitoring of level of drug in blood. If necessary contents of capsules can be dissolved in water and to enter via the nazogastralny probe. It is recommended to distribute a daily oral dose on 2 receptions (in the morning and in the evening). Capsules need to be accepted at once after withdrawal them from the blister packing. Capsules are swallowed, washing down with liquid (it is better water). For achievement of the maximum absorption the drug needs to be taken on an empty stomach or at least for 1 h to or 2–3 h after meal. Influence of the consumption of food on absorption of drug at patients with a kidney transplant is noted. Transplantation of a liver Primary immunosuppression, adults. Oral therapy by the Pro-count begin in a dose 0.1-0.2 mg/kg a day, having distributed this dose on 2 receptions (in the morning and in the evening). To begin use of drug in 12 h after completion of operation. If the condition of the patient does not allow to take the drug inside, carry out in to therapy. Primary immunosuppression, children. The initial dose of drug for oral administration of 0.3 mg/kg a day is distributed on 2 receptions (in the morning and in the evening). If the clinical condition of the patient does not allow to take the drug inside, carry out in to therapy. Maintenance therapy, adults and children. During maintenance therapy the dose of the Pro-count decreases. In certain cases cancel drugs of the accompanying immunosuppressive therapy, having left the Pro-columns as monotherapy. Improvement of a condition of the patient after transplantation can change pharmacokinetics of a takrolimus therefore there is a need for drug dose adjustment. Rejection treatment, adults and children. Apply higher doses of the Pro-count to treatment of rejection, together with additional GKS-therapy and short courses of introduction mono - or polyclonal antibodies. If signs of toxicity are noted, the dose decline of the Pro-count is possible. At convertion of patients the same initial doses are recommended for therapy by the Pro-count, as at primary immunosuppression. At convertion of patients from therapy by cyclosporine on Pro-columns (see. Special INSTRUCTIONS). Transplantation of a kidney Primary immunosuppression, adults. Oral therapy by the Pro-count begin with a dose 0.2-0.3 mg/kg a day, having distributed it on 2 receptions (in the morning and in the evening). Therapy is begun during 24 h after completion of operation. If the condition of the patient does not allow to take the drug inside, carry out in to therapy. Primary immunosuppression, children. Oral therapy by the Pro-count begin with a dose 0.3 mg/kg a day, having distributed this dose on 2 receptions (in the morning and in the evening). If the condition of the patient does not allow to take the drug inside, carry out in to therapy. Maintenance therapy, adults and children. During maintenance therapy the dose of the Pro-count decreases. In certain cases it is possible to cancel drugs of the accompanying immunosuppressive therapy, having left the Pro-columns as basic component of double therapy. Improvement of a condition of the patient after transplantation can change pharmacokinetics of a takrolimus therefore there is a need for drug dose adjustment. Rejection reaction treatment, adults and children. Treatment of rejection requires use of higher doses of the Pro-count, together with additional GKS-therapy and short courses of introduction mono - or polyclonal antibodies. If signs of toxicity are noted, the dose decline of the Pro-count is possible. At convertion of patients the same initial doses are recommended for therapy by the Pro-count, as at primary immunosuppression. At convertion of patients from therapy by cyclosporine on Pro-columns (see. Special INSTRUCTIONS). Transplantation of heart Primary immunosuppression, adults. The pro-count can be applied together with induction by antibodies (taking into account the delayed beginning of therapy by the Pro-count) or without purpose of antibodies at clinically stable condition of patients. After induction oral therapy by the Pro-count begin with antibodies with a dose 0.075 mg/kg a day, having distributed this dose on 2 receptions (in the morning and in the evening). Use of drug needs to be begun for 5 days after completion of operation as soon as the clinical condition of the patient is stabilized. If the condition of the patient does not allow to take the drug inside, carry out in to therapy. There is an alternative approach at which oral administration of a takrolimus begins for 12 h after transplantation. This approach is intended for patients without signs of dysfunctions of internals (kidneys). In this case takrolimus in an initial dose of 2-4 mg/days it is combined from the mikofenolat mofetily both by GKS or sirolimusy and GKS. Primary immunosuppression, children. After transplantation of heart at children primary immunosuppression by the Pro-count can be carried out as in combination with induction by antibodies, and independently. In cases when induction by antibodies is not carried out, the Pro-count is entered in a look in into infusions for 24 h before achievement of concentration of a takrolimus in not divorced blood of 15-25 ng/ml. At the first clinical opportunity it is necessary to transfer the patient to oral administration of drug in an initial dose of 0.3 mg/kg a day which is appointed in 8–12 h after the termination in/in infusion. After induction oral therapy by the Pro-count begin with antibodies with a dose 0.1-0.3 mg/kg a day, having distributed this dose on 2 receptions (in the morning and in the evening). Maintenance therapy, adults and children. At maintenance therapy the dose of the Pro-count decreases. Improvement of a condition of the patient after transplantation can change pharmacokinetics of a takrolimus therefore there is a need for drug dose adjustment. Rejection treatment, adults and children. Treatment of rejection requires use of higher doses of the Pro-count together with additional GKS-therapy and short courses of introduction mono - or polyclonal antibodies. At convertion of adult patients on therapy by the Pro-count the initial dose of drug of 0.15 mg/kg a day is distributed on 2 receptions (in the morning and in the evening). At convertion of children on therapy by the Pro-count the initial dose of drug of 0.2-0.3 mg/kg a day is distributed also on 2 receptions (in the morning and in the evening). Information concerning convertion of patients from therapy by cyclosporine on Pro-columns (see. Special INSTRUCTIONS). The recommended doses after allotransplantation of other bodies. Recommendations concerning the Pro-count's dose for patients after allotransplantation of a lung, a pancreas and intestines are based on data of separate clinical trials. After transplantation of a lung of Pro-columns apply in an initial dose 0.1-0.15 mg/kg a day, allotransplantations of a pancreas — in an initial dose of 0.2 mg/kg a day. Patients have after allotransplantation of intestines an initial dose — 0.3 mg/kg a day. A concentrate for preparation of injection solution. The pro-count the concentrate to preparation of solution for in/in introductions is applied only in / century. It is not necessary to administer the drug not divorced. Before use it it is necessary to part 5% with solution of a dextrose or 0.9% chloride sodium solution in glass, polyethylene or polypropylene bottles. It is necessary to use only transparent and colourless solutions. Jet administration of drug is not recommended. Concentration of solution for infusions has to vary within 0.004-0.1 mg/ml. The total amount of infusion for 24 h has to fluctuate within 20–500 ml. The unused concentrate for infusion in an open ampoule or the unused restored solution needs to be destroyed in order to avoid pollution (contamination). Transplantation of a liver Primary immunosuppression, adults. Use of drug is begun in 12 h after completion of operation. If the condition of the patient does not allow to take the drug inside (capsule), carry out in to therapy since a dose 0.01-0.05 mg/kg a day, entering medicine in a look in into infusions for 24 h. Primary immunosuppression, children. If the condition of the patient does not allow to take the drug inside (capsule), carry out in to therapy since a dose 0.05 mg/kg a day, in a look in/in infusion for 24 h. Maintenance therapy, adults and children. During maintenance therapy the dose of the Pro-count decreases. In certain cases cancel drugs of the accompanying immunosuppressive therapy, applying the Pro-columns as monotherapy. Improvement of a condition of the patient after transplantation can change pharmacokinetics of a takrolimus therefore there is a need for dose adjustment. Rejection treatment, adults and children. Apply higher doses of the Pro-count together with additional GKS-therapy and short courses of introduction to treatment of rejection mono - or polyclonal antibodies. At convertion of adult patients on oral therapy by the Pro-count (capsule) the initial dose of drug of 0.15 mg/kg a day is distributed on 2 receptions (in the morning and in the evening). At convertion of children on oral therapy by the Pro-count the initial dose of 0.2-0.3 mg/kg a day is distributed on 2 receptions (in the morning and in the evening). Information concerning convertion of patients from therapy by cyclosporine on Pro-columns (see. Special INSTRUCTIONS). Transplantation of a kidney Primary immunosuppression, adults. Therapy by drug should be begun for 24 h after the end of operation. If the condition of the patient does not allow to take the drug in (the Pro-count of the capsule), in/in therapy it is necessary to begin 0.05-0.1 mg/kg/days with a dose, administering the drug in a look in/in infusion for 24 h. Primary immunosuppression, children. If the condition of the patient does not allow to take the drug in (the Pro-count of the capsule), in/in therapy it is necessary to begin 0.075-0.1 mg/kg/days with a dose, administering the drug in a look in/in infusion for 24 h. Maintenance therapy, adults and children. During maintenance therapy the dose of the Pro-count is reduced. Cancellation of drugs of the accompanying immunosuppressive therapy is in certain cases possible, having left the Pro-columns as basic component of combination therapy. Improvement of a condition of the patient after transplantation can change pharmacokinetics of a takrolimus therefore there can be a need for drug dose adjustment. Rejection reaction treatment, adults and children. Treatment of episodes of rejection requires use of higher doses of the Pro-count, together with additional therapy by GKS and short courses of introduction of mono/polyclonal antibodies. At emergence of signs of toxicity, there can be necessary a dose decline of the Pro-count.At transfer of patients to therapy by the Pro-count the use of the same initial doses of drug is recommended, as well as at primary immunosuppression. When translating patients from therapy by cyclosporine on Pro-columns (see. Special INSTRUCTIONS). Transplantation of heart Primary immunosuppression, adults. The pro-count is applied together with induction by antibodies (taking into account the delayed beginning of therapy by the Pro-count). After induction by antibodies administration of drug should be begun within 5 days after completion of operation after stabilization of a clinical condition of the patient. If the condition of the patient does not allow to take the drug in (the Pro-count of the capsule), carry out in to therapy, since a dose of 0.01-0.02 mg/kg/days, administering the drug in a look in/in infusion for 24 h. Primary immunosuppression, children. After transplantation of heart at children primary immunosuppression by the Pro-count can be carried out as together with induction by antibodies, and independently. In cases when induction by antibodies is not carried out, the Pro-count is entered in/in in an initial dose of 0.03-0.05 mg/kg/days, in a look in into infusions for 24 h before achievement of concentration of a takrolimus in not divorced blood of 15-25 ng/ml. At a clinical opportunity it is necessary to transfer the patient to oral administration of drug (Pro-count of the capsule) in an initial dose of 0.30 mg/kg/days with an interval of 8-12 h after the termination in/in infusions. Maintenance therapy, adults and children. During maintenance therapy of a dose of the Pro-count decrease. Improvement of a condition of the patient after transplantation can change pharmacokinetics of a takrolimus therefore there can be a need for drug dose adjustment. Rejection treatment, adults and children. Treatment of episodes of rejection requires use of higher doses of the Pro-count together with additional therapy by GKS and short courses of introduction of mono/polyclonal antibodies. At transfer of adult patients to oral therapy by the Pro-count (capsule) the initial dose of drug of 0.15 mg/kg/days should be distributed on 2 receptions (for example in the morning and in the evening). At transfer of children to oral therapy by the Pro-count (capsule) the initial dose of drug of 0.2-0.3 mg/kg/days should be distributed on 2 receptions (for example in the morning and in the evening). Information concerning the translation of patients from therapy by cyclosporine on Pro-columns see. Special INSTRUCTIONS). The recommended doses after allotransplantation of other bodies. Recommendations concerning dosing of the Pro-count for patients after allotransplantation of a lung, a pancreas and intestines are based on data of clinical trials. After transplantation of a lung of Pro-columns it is applied in an initial dose of 0.1-0.15 mg/kg a day, allotransplantation of a pancreas — in an initial dose of 0.2 mg/kg a day. Patients have after allotransplantation of intestines an initial dose — 0.3 mg/kg a day.
CONTRAINDICATIONS: hypersensitivity to a takrolimus (or to other macroleads) and to other inactive ingredients of drug.
SIDE EFFECTS: the majority of the side reactions given below are reversible and/or their expressiveness decreases at a dose decline. At oral administration the frequency of side effects is lower, than at in in introduction. The following reactions are given depending on emergence frequency: very often (1/10), it is frequent (1/100, but ≤1/10), sometimes (1/1000, but ≤1/100), is rare (1/10,000, but ≤1/1000), is very rare (≤1/10,000, including isolated cases). From a cardiovascular system: very often — AG, is frequent — arterial hypotension, tachycardia, arrhythmias and disturbances of warm conductivity, thromboembolic and ischemic manifestations, stenocardia, a disease of vessels, sometimes — deviations on the ECG, a heart attack, heart failure, shock, a myocardium hypertrophy, cardiac arrest.From a GIT and a liver: very often — diarrhea, nausea and/or vomiting, it is frequent — dysfunction of a GIT (dyspepsia), a deviation in levels of enzymes of a liver, an abdominal pain, a constipation, change of body weight and appetite, inflammation and ulcers in a GIT, jaundice, diseases of bilious ways and a gall bladder, sometimes — ascites, intestinal impassability (Ilheus), defeat of a parenchyma of a liver, pancreatitis, is rare — a liver failure. From the system of blood: often — anemia, a leukopenia, thrombocytopenia, a hemorrhage, a leukocytosis, coagulation disturbance, sometimes — insufficiency of a gematopoetichesky system, including a pancytopenia, a trombotichesky mikroangiopatiya.Co of the side of an urinary system: very often — the renal failure (increase in level of creatinine in blood serum), is frequent — defeat of tissue of kidneys, a renal failure, sometimes — a proteinuria. From a metabolism and laboratory indicators: very often — a hyperglycemia, a hyperpotassemia, diabetes, it is frequent — a hypomagnesiemia, a lipidemia, a hypophosphatemia, a hypopotassemia, a hyperuricemia, a hypocalcemia, acidosis, a hyponatremia, a hypovolemia, other disturbances of electrolytic balance, dehydration, sometimes — a hypoproteinuria, a hyperphosphatemia, increase in level of amylase, a hypoglycemia. From a musculoskeletal system: often — spasms, sometimes — a myasthenia, a disease of joints. From nervous system and sense bodys: very often — a tremor, a headache, insomnia, it is frequent — disturbance of sensitivity (paresthesia), a disorder of vision, confusion of consciousness, a depression, dizziness, excitement, neuropathy, spasms, a diskoordination, psychosis, uneasiness, nervousness, a sleep disorder, consciousnesses, emotional lability, hallucinations, otological disturbances, disturbance of thinking, encephalopathy, sometimes — increase in a muscle tone, a disease of eyes, amnesia, a cataract, disturbance of the speech, paralysis, a coma, deafness, is very rare — a blindness. From a respiratory system: often — disturbance of respiratory function (asthma), a pleural exudate, sometimes — atelectases, OH. From skin: often — an itching, an alopecia, rash, perspiration, an acne, a fotosensibillization, sometimes — a hirsutism, it is rare — a Lyell's disease, is very rare — Stephens's syndrome — Johnson. From the immune system. At the patients accepting takrolimus allergic and anaphylactic reactions were noted. Besides, the patients receiving immunosuppressive therapy enter into group of the increased risk of developing malignant tumors. At use of a takrolimus the development of both the benign, and malignant tumors including associated with Epstein's virus — Barre (EBV) of limfoproliferativny diseases and a carcinoma cutaneum is noted. Risk of developing infectious diseases (virus, bacterial, fungal, protozoan) also increases. The course of earlier diagnosed infectious diseases can worsen. General manifestations: very often — the localized pain (arthralgia), it is frequent — fever, peripheral hypostasis, an asthenia, urination disturbance, sometimes — hypostasis and other disturbances from genitalias at women. In isolated cases noted development of a hypertrophy of a ventricle or hypertrophy of an interventricular partition of heart, registered as cardiomyopathy. In most cases these manifestations were reversible, developing generally at children with the minimum concentration of a takrolimus in the blood much exceeding the recommended maximum levels. Earlier existing heart diseases, reception of GKS, AG, dysfunction of kidneys or a liver, an infection, surplus of liquid in an organism and hypostases were other factors increasing risk of development of such clinical states. As well as at use of other potential immunosuppressive drugs, at patients, the accepting Pro-columns, development EBV лимфопролиферативных of disturbances is noted. It can be caused by excess immunosuppression prior to drug use in patients who were transferred to therapy by the Pro-count. The accompanying reception of anti-lymphocytic therapy was forbidden patients who were transferred to therapy by the Pro-count. At children (aged from 2 years) with EBV seronegative reaction the increased risk of developing limfoproliferativny diseases is noted (this group of patients prior to use of the Pro-count requires serological definition of the EBV virus).
SPECIAL INSTRUCTIONS: Dose adjustment of drug in special groups of patients. The dose decline can be required by patients with a heavy liver failure to support the minimum level of drug within the recommended gradation. As the pharmacokinetics of a takrolimus does not change depending on function of kidneys, dose adjustment is not necessary to patients with a renal failure. However in connection with existence at a takrolimus of nephrotoxic action it is recommended to control carefully function of kidneys (including concentration of creatinine in blood serum, clearance of creatinine and level of a diuresis). For achievement of necessary levels of drug in blood children need doses in 1, 5–2 times above, than the adult. There is no need of dose adjustment given relatively for patients of advanced age. Transition from therapy by cyclosporine. The accompanying use of cyclosporine and the Pro-count can extend elimination half-life of cyclosporine and enhance toxic effects. Therefore it is necessary to adhere to care at convertion of patients from cyclosporine on therapy by the Pro-count. Treatment by the Pro-count is begun after assessment of concentration of cyclosporine in blood of the patient and his clinical state. Administration of drug is stopped at the increased cyclosporine level in blood. In practice the treatment by the Pro-count was begun in 12–24 h after the termination of intake of cyclosporine. After convertion of the patient it is necessary to continue monitoring of levels of cyclosporine in the patient's blood in connection with a possibility of disturbance of clearance of cyclosporine. Recommendations concerning achievement of necessary level of concentration of drug in not divorced blood. The choice of a dose of drug has to be based on results of clinical assessment of process of rejection and tolerance of drug by each patient individually. For optimization of a dosage of drug the definition of concentration of a takrolimus in not divorced blood by means of immune methods, including semi-automatic enzyme immunoassay on microparticles (MYTH) is used. Comparison of the data on concentration of a takrolimus in blood published in literature with individual clinical indicators carry out estimates which was applied on the basis of a method. During the early period after operation control the minimum levels of a takrolimus in not divorced blood. At oral administration for determination of the minimum levels of drug in blood it is necessary to receive blood samples in 12 h after its reception, directly before use of the following dose. Frequency of monitoring of level of drug in blood depends on clinical need. As the Pro-count is drug with the low level of clearance, correction of dosing can take several days until when changes of levels of drug in blood become obvious. The minimum levels of drug in blood control 2 times a week throughout the early post-transplant period and periodically during maintenance therapy. It is also necessary to control the minimum levels of a takrolimus in blood after change of a dose of drug, the immunosuppressive mode or after combined use with drugs which can affect concentration of a takrolimus in not divorced blood. Results of clinical trials allow to assume that it is possible to carry out successfully treatment of most of patients if the minimum levels of a takrolimus in blood are maintained lower than 20 ng/ml. Interpreting data on concentration of drug in not divorced blood, it is important to estimate a clinical condition of the patient. In clinical practice throughout the early period after transplantation the minimum levels of drug in not divorced blood usually fluctuated within 5–20 ng/ml after transplantation of a liver and 10–20 ng/ml after transplantation of a kidney and heart. Further during maintenance therapy after transplantation of a liver, kidneys and heart of concentration of drug in blood vary from 5 to 15 ng/ml. During an initial stage after performing transplantation it is necessary to carry out routine monitoring of such parameters: The ABP, the ECG, the neurologic and visual status, glucose level in blood on an empty stomach, electrolytes (especially potassium), function of a liver and kidneys, parameters of complete blood count test, indicators of coagulation and definition of protein fractions in blood plasma. As well as at use of other immunosuppressive drugs, owing to potential risk of development of malignant changes on skin it is necessary to limit influence of sunshine and ultraviolet radiation, protecting skin clothes and using creams with a high factor of protection. Takrolimus is incompatible with polyvinylchloride. If contents of capsules need to be entered via the nazogastralny probe, the last should not contain polyvinylchloride. Grapefruit juice increases the level of a takrolimus in blood at the expense of inhibition of activity of CYP 3A4. Takrolimus can cause visual and neurologic disturbances. Patients at whom such disturbances developed should not run vehicles or work with mechanisms. This influence can amplify at a concomitant use of the Pro-count with alcohol. Drug can get through a placenta. As safety of use of the Pro-count for pregnant women is not established, it is not necessary to appoint this drug during pregnancy, except for cases when the expected advantage of treatment exceeds potential risk for a fruit. Takrolimus is allocated with breast milk. As it is impossible to exclude negative influence on children of chest age, the women taking the drug have to stop feeding by a breast.
INTERACTIONS: Pharmacokinetic interactions. Takrolimus is substantially metabolized by hepatic microsomal P450 3A4 cytochrome isoenzyme (CYP 3A4). The accompanying intake of the medicines or drugs of plant origin inhibiting or inducing CYP 3A4 can influence metabolism of a takrolimus and lower or increase levels of a takrolimus in blood. Takrolimus influences CYP 3A4-dependent metabolism, combined use of a takrolimus with drugs which are metabolized by CYP in the 3A4-dependent ways, can influence metabolism of these drugs (cortisone, testosterone). Takrolimus considerably contacts proteins of blood plasma. It is necessary to consider possible interactions with other drugs which are vysokoafinny to blood proteins (NPVP, oral anticoagulants or oral antidiabetic drugs). Pharmakodinamichesky interactions. The accompanying reception of a takrolimus with the drugs having nephrotoxic or neurotoxic effects can increase toxicity level (aminoglycosides, giraza inhibitors (sort DNA-topoisomerase II), Vancomycinum, co-trimoxazole, NPVP, gantsiklovir or acyclovir). As treatment takrolimusy can be followed by development of a hyperpotassemia or can strengthen earlier existing hyperpotassemia, it is necessary to avoid excess intake of potassium, use of kaliysberegayushchy diuretics (amiloride, Triamterenum or Spironolactonum). Other interactions. During use of a takrolimus the efficiency of vaccines decreases and it is necessary to avoid administration of live attenuirovanny vaccines. Clinically significant interactions. The drugs marked with an asterisk need changes of doses of a takrolimus practically at all patients. Other drugs which are given below can need correction of a dosage in some cases. The drugs inhibiting CYP 3A4 and increasing levels of a takrolimus in blood: ketokonazol *, flukonazol *, itrakonazol *, Clotrimazolum, vorikonazol *, nifedipine, nikardipin, erythromycin *, klaritromitsin, dzhozamitsin, inhibitors of HIV proteases, danazol, et
kaps. 0.5 mg, No. 50
Takrolimus
of 0.5 mg
Other ingredients: a hydroksipropilmetiltsellyuloza, sodium of a kroskarmelloz, lactose, magnesium stearate, the titan dioxide (E171), gelatin, iron oxide yellow, sodium lauryl sulfate, water purified.
No. UA/4994/02/01 from 18.08.2006 till 18.08.2011
kaps. 1 mg, No. 50
Takrolimus
of 1 mg
Other ingredients: a hydroksipropilmetiltsellyuloza, sodium of a kroskarmelloz, lactose, magnesium stearate, the titan dioxide (E171), gelatin, sodium lauryl sulfate, water purified.
No. UA/4994/02/02 from 18.08.2006 till 18.08.2011
kaps. 5 mg, No. 50
Takrolimus
of 5 mg
Other ingredients: a hydroksipropilmetiltsellyuloza, sodium of a kroskarmelloz, lactose, magnesium stearate, the titan dioxide (E171), gelatin, ferrous oxide red, sodium lauryl sulfate, water purified.
No. UA/4994/02/03 from 18.08.2006 till 18.08.2011
konts. baby solution for infection. in/in 5 mg/ml of amp. 1 ml, No. 10
Takrolimus
of 5 mg/ml
Other ingredients: the castor oil hydrogenated by polyoxyethylene 60, anhydrous alcohol.
No. UA/4994/01/01 from 18.08.2006 till 18.08.2011
PHARMACOLOGICAL PROPERTIES: at molecular level the effects of a takrolimus are predetermined by linking with cytosolic protein (FKBP12) which is responsible for intracellular cumulation of drug. The FKBP12-takrolimus complex specifically and competitively communicates with kaltsinevriny and inhibits it that leads to kaltsiyzavisimy inhibition of T-cellular alarm ways of transduction, thus prevents a transcription of discrete group of limfokinny genes. Takrolimus represents highly active immunosuppressive substance, the oppressing forming of cytotoxic lymphocytes which generally are responsible for graft rejection, reduce activation of T-cells, proliferation of V-cells, dependent on T-helperov, and also forming of lymphokines (such as interleukins-2,-3 and γ-interferon), an interleukin-2 receptor expression. Capsules of a takrolimus it is absorbed from a GIT, the main place of absorption is the upper part of a GIT. The maximum concentration in blood plasma (Cmax) of a takrolimus reach peak (Tmax) approximately in 1–3 h. At some patients drug is absorbed throughout the long period, reaching rather uniform profile of absorption. The average value of parameters of absorption is given below:
Population
Dosing (mg/kg/days)
of Cmax (ng/ml)
of Tmax (ch)
Bioavailability (%)
the Transplant of a liver of the adult (equilibrium concentration)
0,30 74,1 3,0 21,8 (±6,3)
Transplant of a liver of the child (equilibrium concentration)
0,30 37,0 (±26,5) 2,1 (±1,3) 25 (±20)
Transplant of a kidney of the adult (equilibrium concentration)
0,30 44,3 (±21,9) 1,5 20,1 (±11,0)
After oral administration (0.3 mg/kg a day) drug at patients with a liver transplant at most of patients the equilibrium concentration were reached for 3 days. At patients with a liver transplant in a stable state the bioavailability of the Pro-count decreased at oral administration of drug after consumption of food with the moderate content of fats. Also decrease in AUC (27%), Cmax (50%) and increase in Tmax (173%) in not divorced blood was noted. At simultaneous use of drug with food the speed and extent of absorption of the Pro-count decreased. Biliation does not influence drug absorption. The considerable correlation between AUC and the minimum levels of drug in not divorced blood at achievement of an equilibrium state in this connection monitoring of the minimum levels of drug in not divorced blood can help with adequate assessment of system influence of drug is noted. The nature of distribution of a takrolimus in/in introductions can be described later as two-phase. In a system blood-groove takrolimus considerably contacts erythrocytes. A ratio not divorced blood / concentration in blood plasma makes 20:1. In blood plasma drug considerably contacts (98.8%) proteins, generally with serumal albumine and a α-1-kisly glycoprotein. Takrolimus widely extends in an organism. The equilibrium volume of distribution (on the basis of concentration in blood plasma) — 1300 l (healthy volunteers). The corresponding indicator on the basis of not divorced blood — 47.6 l. Takrolimus — substance with the low level of clearance. Healthy volunteers have an average value of the general clearance which is estimated on concentration of drug in not divorced blood — 2.25 l/h. Adult patients with a transplant of a liver and kidneys have a value of this parameter — 4.1 and 6.7 l/h respectively. At children with a transplant of a liver of value of the general clearance is twice higher, than at adult patients with a liver transplant. The period semi-removal of a takrolimus is long and changeable. Healthy volunteers have an average value of elimination half-life from not divorced blood — 43 h. Adult patients and children with a transplant of a liver have an elimination half-life on average 11.7 and 12.4 h respectively, in comparison with 15.6 h at adult patients with a kidney transplant. When using in vitro of models 8 metabolites among which only 1 has important immunosuppressive activity are revealed. Takrolimus is considerably metabolized by hepatic microsomal P450 3A4 cytochrome CYP isoenzyme 3A4. After oral introduction of a takrolimus, marked 14C isotope, the majority radioactive mechennogo drug was removed with a stake. About 2% are removed with urine. Less than 1% of not changed takrolimus were noted in urine and Calais, it indicates that it takrolimus is almost completely metabolized before elimination. The main way of elimination — bile.
INDICATIONS: prevention and treatment of rejection of allograft of a liver, kidneys and heart, including resistant to the standard modes of immunosuppressive therapy.
USE: capsules accept inside. Dosing needs to be adjusted depending on specific features of an organism of the patient, considering results of monitoring of level of drug in blood. If necessary contents of capsules can be dissolved in water and to enter via the nazogastralny probe. It is recommended to distribute a daily oral dose on 2 receptions (in the morning and in the evening). Capsules need to be accepted at once after withdrawal them from the blister packing. Capsules are swallowed, washing down with liquid (it is better water). For achievement of the maximum absorption the drug needs to be taken on an empty stomach or at least for 1 h to or 2–3 h after meal. Influence of the consumption of food on absorption of drug at patients with a kidney transplant is noted. Transplantation of a liver Primary immunosuppression, adults. Oral therapy by the Pro-count begin in a dose 0.1-0.2 mg/kg a day, having distributed this dose on 2 receptions (in the morning and in the evening). To begin use of drug in 12 h after completion of operation. If the condition of the patient does not allow to take the drug inside, carry out in to therapy. Primary immunosuppression, children. The initial dose of drug for oral administration of 0.3 mg/kg a day is distributed on 2 receptions (in the morning and in the evening). If the clinical condition of the patient does not allow to take the drug inside, carry out in to therapy. Maintenance therapy, adults and children. During maintenance therapy the dose of the Pro-count decreases. In certain cases cancel drugs of the accompanying immunosuppressive therapy, having left the Pro-columns as monotherapy. Improvement of a condition of the patient after transplantation can change pharmacokinetics of a takrolimus therefore there is a need for drug dose adjustment. Rejection treatment, adults and children. Apply higher doses of the Pro-count to treatment of rejection, together with additional GKS-therapy and short courses of introduction mono - or polyclonal antibodies. If signs of toxicity are noted, the dose decline of the Pro-count is possible. At convertion of patients the same initial doses are recommended for therapy by the Pro-count, as at primary immunosuppression. At convertion of patients from therapy by cyclosporine on Pro-columns (see. Special INSTRUCTIONS). Transplantation of a kidney Primary immunosuppression, adults. Oral therapy by the Pro-count begin with a dose 0.2-0.3 mg/kg a day, having distributed it on 2 receptions (in the morning and in the evening). Therapy is begun during 24 h after completion of operation. If the condition of the patient does not allow to take the drug inside, carry out in to therapy. Primary immunosuppression, children. Oral therapy by the Pro-count begin with a dose 0.3 mg/kg a day, having distributed this dose on 2 receptions (in the morning and in the evening). If the condition of the patient does not allow to take the drug inside, carry out in to therapy. Maintenance therapy, adults and children. During maintenance therapy the dose of the Pro-count decreases. In certain cases it is possible to cancel drugs of the accompanying immunosuppressive therapy, having left the Pro-columns as basic component of double therapy. Improvement of a condition of the patient after transplantation can change pharmacokinetics of a takrolimus therefore there is a need for drug dose adjustment. Rejection reaction treatment, adults and children. Treatment of rejection requires use of higher doses of the Pro-count, together with additional GKS-therapy and short courses of introduction mono - or polyclonal antibodies. If signs of toxicity are noted, the dose decline of the Pro-count is possible. At convertion of patients the same initial doses are recommended for therapy by the Pro-count, as at primary immunosuppression. At convertion of patients from therapy by cyclosporine on Pro-columns (see. Special INSTRUCTIONS). Transplantation of heart Primary immunosuppression, adults. The pro-count can be applied together with induction by antibodies (taking into account the delayed beginning of therapy by the Pro-count) or without purpose of antibodies at clinically stable condition of patients. After induction oral therapy by the Pro-count begin with antibodies with a dose 0.075 mg/kg a day, having distributed this dose on 2 receptions (in the morning and in the evening). Use of drug needs to be begun for 5 days after completion of operation as soon as the clinical condition of the patient is stabilized. If the condition of the patient does not allow to take the drug inside, carry out in to therapy. There is an alternative approach at which oral administration of a takrolimus begins for 12 h after transplantation. This approach is intended for patients without signs of dysfunctions of internals (kidneys). In this case takrolimus in an initial dose of 2-4 mg/days it is combined from the mikofenolat mofetily both by GKS or sirolimusy and GKS. Primary immunosuppression, children. After transplantation of heart at children primary immunosuppression by the Pro-count can be carried out as in combination with induction by antibodies, and independently. In cases when induction by antibodies is not carried out, the Pro-count is entered in a look in into infusions for 24 h before achievement of concentration of a takrolimus in not divorced blood of 15-25 ng/ml. At the first clinical opportunity it is necessary to transfer the patient to oral administration of drug in an initial dose of 0.3 mg/kg a day which is appointed in 8–12 h after the termination in/in infusion. After induction oral therapy by the Pro-count begin with antibodies with a dose 0.1-0.3 mg/kg a day, having distributed this dose on 2 receptions (in the morning and in the evening). Maintenance therapy, adults and children. At maintenance therapy the dose of the Pro-count decreases. Improvement of a condition of the patient after transplantation can change pharmacokinetics of a takrolimus therefore there is a need for drug dose adjustment. Rejection treatment, adults and children. Treatment of rejection requires use of higher doses of the Pro-count together with additional GKS-therapy and short courses of introduction mono - or polyclonal antibodies. At convertion of adult patients on therapy by the Pro-count the initial dose of drug of 0.15 mg/kg a day is distributed on 2 receptions (in the morning and in the evening). At convertion of children on therapy by the Pro-count the initial dose of drug of 0.2-0.3 mg/kg a day is distributed also on 2 receptions (in the morning and in the evening). Information concerning convertion of patients from therapy by cyclosporine on Pro-columns (see. Special INSTRUCTIONS). The recommended doses after allotransplantation of other bodies. Recommendations concerning the Pro-count's dose for patients after allotransplantation of a lung, a pancreas and intestines are based on data of separate clinical trials. After transplantation of a lung of Pro-columns apply in an initial dose 0.1-0.15 mg/kg a day, allotransplantations of a pancreas — in an initial dose of 0.2 mg/kg a day. Patients have after allotransplantation of intestines an initial dose — 0.3 mg/kg a day. A concentrate for preparation of injection solution. The pro-count the concentrate to preparation of solution for in/in introductions is applied only in / century. It is not necessary to administer the drug not divorced. Before use it it is necessary to part 5% with solution of a dextrose or 0.9% chloride sodium solution in glass, polyethylene or polypropylene bottles. It is necessary to use only transparent and colourless solutions. Jet administration of drug is not recommended. Concentration of solution for infusions has to vary within 0.004-0.1 mg/ml. The total amount of infusion for 24 h has to fluctuate within 20–500 ml. The unused concentrate for infusion in an open ampoule or the unused restored solution needs to be destroyed in order to avoid pollution (contamination). Transplantation of a liver Primary immunosuppression, adults. Use of drug is begun in 12 h after completion of operation. If the condition of the patient does not allow to take the drug inside (capsule), carry out in to therapy since a dose 0.01-0.05 mg/kg a day, entering medicine in a look in into infusions for 24 h. Primary immunosuppression, children. If the condition of the patient does not allow to take the drug inside (capsule), carry out in to therapy since a dose 0.05 mg/kg a day, in a look in/in infusion for 24 h. Maintenance therapy, adults and children. During maintenance therapy the dose of the Pro-count decreases. In certain cases cancel drugs of the accompanying immunosuppressive therapy, applying the Pro-columns as monotherapy. Improvement of a condition of the patient after transplantation can change pharmacokinetics of a takrolimus therefore there is a need for dose adjustment. Rejection treatment, adults and children. Apply higher doses of the Pro-count together with additional GKS-therapy and short courses of introduction to treatment of rejection mono - or polyclonal antibodies. At convertion of adult patients on oral therapy by the Pro-count (capsule) the initial dose of drug of 0.15 mg/kg a day is distributed on 2 receptions (in the morning and in the evening). At convertion of children on oral therapy by the Pro-count the initial dose of 0.2-0.3 mg/kg a day is distributed on 2 receptions (in the morning and in the evening). Information concerning convertion of patients from therapy by cyclosporine on Pro-columns (see. Special INSTRUCTIONS). Transplantation of a kidney Primary immunosuppression, adults. Therapy by drug should be begun for 24 h after the end of operation. If the condition of the patient does not allow to take the drug in (the Pro-count of the capsule), in/in therapy it is necessary to begin 0.05-0.1 mg/kg/days with a dose, administering the drug in a look in/in infusion for 24 h. Primary immunosuppression, children. If the condition of the patient does not allow to take the drug in (the Pro-count of the capsule), in/in therapy it is necessary to begin 0.075-0.1 mg/kg/days with a dose, administering the drug in a look in/in infusion for 24 h. Maintenance therapy, adults and children. During maintenance therapy the dose of the Pro-count is reduced. Cancellation of drugs of the accompanying immunosuppressive therapy is in certain cases possible, having left the Pro-columns as basic component of combination therapy. Improvement of a condition of the patient after transplantation can change pharmacokinetics of a takrolimus therefore there can be a need for drug dose adjustment. Rejection reaction treatment, adults and children. Treatment of episodes of rejection requires use of higher doses of the Pro-count, together with additional therapy by GKS and short courses of introduction of mono/polyclonal antibodies. At emergence of signs of toxicity, there can be necessary a dose decline of the Pro-count.At transfer of patients to therapy by the Pro-count the use of the same initial doses of drug is recommended, as well as at primary immunosuppression. When translating patients from therapy by cyclosporine on Pro-columns (see. Special INSTRUCTIONS). Transplantation of heart Primary immunosuppression, adults. The pro-count is applied together with induction by antibodies (taking into account the delayed beginning of therapy by the Pro-count). After induction by antibodies administration of drug should be begun within 5 days after completion of operation after stabilization of a clinical condition of the patient. If the condition of the patient does not allow to take the drug in (the Pro-count of the capsule), carry out in to therapy, since a dose of 0.01-0.02 mg/kg/days, administering the drug in a look in/in infusion for 24 h. Primary immunosuppression, children. After transplantation of heart at children primary immunosuppression by the Pro-count can be carried out as together with induction by antibodies, and independently. In cases when induction by antibodies is not carried out, the Pro-count is entered in/in in an initial dose of 0.03-0.05 mg/kg/days, in a look in into infusions for 24 h before achievement of concentration of a takrolimus in not divorced blood of 15-25 ng/ml. At a clinical opportunity it is necessary to transfer the patient to oral administration of drug (Pro-count of the capsule) in an initial dose of 0.30 mg/kg/days with an interval of 8-12 h after the termination in/in infusions. Maintenance therapy, adults and children. During maintenance therapy of a dose of the Pro-count decrease. Improvement of a condition of the patient after transplantation can change pharmacokinetics of a takrolimus therefore there can be a need for drug dose adjustment. Rejection treatment, adults and children. Treatment of episodes of rejection requires use of higher doses of the Pro-count together with additional therapy by GKS and short courses of introduction of mono/polyclonal antibodies. At transfer of adult patients to oral therapy by the Pro-count (capsule) the initial dose of drug of 0.15 mg/kg/days should be distributed on 2 receptions (for example in the morning and in the evening). At transfer of children to oral therapy by the Pro-count (capsule) the initial dose of drug of 0.2-0.3 mg/kg/days should be distributed on 2 receptions (for example in the morning and in the evening). Information concerning the translation of patients from therapy by cyclosporine on Pro-columns see. Special INSTRUCTIONS). The recommended doses after allotransplantation of other bodies. Recommendations concerning dosing of the Pro-count for patients after allotransplantation of a lung, a pancreas and intestines are based on data of clinical trials. After transplantation of a lung of Pro-columns it is applied in an initial dose of 0.1-0.15 mg/kg a day, allotransplantation of a pancreas — in an initial dose of 0.2 mg/kg a day. Patients have after allotransplantation of intestines an initial dose — 0.3 mg/kg a day.
CONTRAINDICATIONS: hypersensitivity to a takrolimus (or to other macroleads) and to other inactive ingredients of drug.
SIDE EFFECTS: the majority of the side reactions given below are reversible and/or their expressiveness decreases at a dose decline. At oral administration the frequency of side effects is lower, than at in in introduction. The following reactions are given depending on emergence frequency: very often (1/10), it is frequent (1/100, but ≤1/10), sometimes (1/1000, but ≤1/100), is rare (1/10,000, but ≤1/1000), is very rare (≤1/10,000, including isolated cases). From a cardiovascular system: very often — AG, is frequent — arterial hypotension, tachycardia, arrhythmias and disturbances of warm conductivity, thromboembolic and ischemic manifestations, stenocardia, a disease of vessels, sometimes — deviations on the ECG, a heart attack, heart failure, shock, a myocardium hypertrophy, cardiac arrest.From a GIT and a liver: very often — diarrhea, nausea and/or vomiting, it is frequent — dysfunction of a GIT (dyspepsia), a deviation in levels of enzymes of a liver, an abdominal pain, a constipation, change of body weight and appetite, inflammation and ulcers in a GIT, jaundice, diseases of bilious ways and a gall bladder, sometimes — ascites, intestinal impassability (Ilheus), defeat of a parenchyma of a liver, pancreatitis, is rare — a liver failure. From the system of blood: often — anemia, a leukopenia, thrombocytopenia, a hemorrhage, a leukocytosis, coagulation disturbance, sometimes — insufficiency of a gematopoetichesky system, including a pancytopenia, a trombotichesky mikroangiopatiya.Co of the side of an urinary system: very often — the renal failure (increase in level of creatinine in blood serum), is frequent — defeat of tissue of kidneys, a renal failure, sometimes — a proteinuria. From a metabolism and laboratory indicators: very often — a hyperglycemia, a hyperpotassemia, diabetes, it is frequent — a hypomagnesiemia, a lipidemia, a hypophosphatemia, a hypopotassemia, a hyperuricemia, a hypocalcemia, acidosis, a hyponatremia, a hypovolemia, other disturbances of electrolytic balance, dehydration, sometimes — a hypoproteinuria, a hyperphosphatemia, increase in level of amylase, a hypoglycemia. From a musculoskeletal system: often — spasms, sometimes — a myasthenia, a disease of joints. From nervous system and sense bodys: very often — a tremor, a headache, insomnia, it is frequent — disturbance of sensitivity (paresthesia), a disorder of vision, confusion of consciousness, a depression, dizziness, excitement, neuropathy, spasms, a diskoordination, psychosis, uneasiness, nervousness, a sleep disorder, consciousnesses, emotional lability, hallucinations, otological disturbances, disturbance of thinking, encephalopathy, sometimes — increase in a muscle tone, a disease of eyes, amnesia, a cataract, disturbance of the speech, paralysis, a coma, deafness, is very rare — a blindness. From a respiratory system: often — disturbance of respiratory function (asthma), a pleural exudate, sometimes — atelectases, OH. From skin: often — an itching, an alopecia, rash, perspiration, an acne, a fotosensibillization, sometimes — a hirsutism, it is rare — a Lyell's disease, is very rare — Stephens's syndrome — Johnson. From the immune system. At the patients accepting takrolimus allergic and anaphylactic reactions were noted. Besides, the patients receiving immunosuppressive therapy enter into group of the increased risk of developing malignant tumors. At use of a takrolimus the development of both the benign, and malignant tumors including associated with Epstein's virus — Barre (EBV) of limfoproliferativny diseases and a carcinoma cutaneum is noted. Risk of developing infectious diseases (virus, bacterial, fungal, protozoan) also increases. The course of earlier diagnosed infectious diseases can worsen. General manifestations: very often — the localized pain (arthralgia), it is frequent — fever, peripheral hypostasis, an asthenia, urination disturbance, sometimes — hypostasis and other disturbances from genitalias at women. In isolated cases noted development of a hypertrophy of a ventricle or hypertrophy of an interventricular partition of heart, registered as cardiomyopathy. In most cases these manifestations were reversible, developing generally at children with the minimum concentration of a takrolimus in the blood much exceeding the recommended maximum levels. Earlier existing heart diseases, reception of GKS, AG, dysfunction of kidneys or a liver, an infection, surplus of liquid in an organism and hypostases were other factors increasing risk of development of such clinical states. As well as at use of other potential immunosuppressive drugs, at patients, the accepting Pro-columns, development EBV лимфопролиферативных of disturbances is noted. It can be caused by excess immunosuppression prior to drug use in patients who were transferred to therapy by the Pro-count. The accompanying reception of anti-lymphocytic therapy was forbidden patients who were transferred to therapy by the Pro-count. At children (aged from 2 years) with EBV seronegative reaction the increased risk of developing limfoproliferativny diseases is noted (this group of patients prior to use of the Pro-count requires serological definition of the EBV virus).
SPECIAL INSTRUCTIONS: Dose adjustment of drug in special groups of patients. The dose decline can be required by patients with a heavy liver failure to support the minimum level of drug within the recommended gradation. As the pharmacokinetics of a takrolimus does not change depending on function of kidneys, dose adjustment is not necessary to patients with a renal failure. However in connection with existence at a takrolimus of nephrotoxic action it is recommended to control carefully function of kidneys (including concentration of creatinine in blood serum, clearance of creatinine and level of a diuresis). For achievement of necessary levels of drug in blood children need doses in 1, 5–2 times above, than the adult. There is no need of dose adjustment given relatively for patients of advanced age. Transition from therapy by cyclosporine. The accompanying use of cyclosporine and the Pro-count can extend elimination half-life of cyclosporine and enhance toxic effects. Therefore it is necessary to adhere to care at convertion of patients from cyclosporine on therapy by the Pro-count. Treatment by the Pro-count is begun after assessment of concentration of cyclosporine in blood of the patient and his clinical state. Administration of drug is stopped at the increased cyclosporine level in blood. In practice the treatment by the Pro-count was begun in 12–24 h after the termination of intake of cyclosporine. After convertion of the patient it is necessary to continue monitoring of levels of cyclosporine in the patient's blood in connection with a possibility of disturbance of clearance of cyclosporine. Recommendations concerning achievement of necessary level of concentration of drug in not divorced blood. The choice of a dose of drug has to be based on results of clinical assessment of process of rejection and tolerance of drug by each patient individually. For optimization of a dosage of drug the definition of concentration of a takrolimus in not divorced blood by means of immune methods, including semi-automatic enzyme immunoassay on microparticles (MYTH) is used. Comparison of the data on concentration of a takrolimus in blood published in literature with individual clinical indicators carry out estimates which was applied on the basis of a method. During the early period after operation control the minimum levels of a takrolimus in not divorced blood. At oral administration for determination of the minimum levels of drug in blood it is necessary to receive blood samples in 12 h after its reception, directly before use of the following dose. Frequency of monitoring of level of drug in blood depends on clinical need. As the Pro-count is drug with the low level of clearance, correction of dosing can take several days until when changes of levels of drug in blood become obvious. The minimum levels of drug in blood control 2 times a week throughout the early post-transplant period and periodically during maintenance therapy. It is also necessary to control the minimum levels of a takrolimus in blood after change of a dose of drug, the immunosuppressive mode or after combined use with drugs which can affect concentration of a takrolimus in not divorced blood. Results of clinical trials allow to assume that it is possible to carry out successfully treatment of most of patients if the minimum levels of a takrolimus in blood are maintained lower than 20 ng/ml. Interpreting data on concentration of drug in not divorced blood, it is important to estimate a clinical condition of the patient. In clinical practice throughout the early period after transplantation the minimum levels of drug in not divorced blood usually fluctuated within 5–20 ng/ml after transplantation of a liver and 10–20 ng/ml after transplantation of a kidney and heart. Further during maintenance therapy after transplantation of a liver, kidneys and heart of concentration of drug in blood vary from 5 to 15 ng/ml. During an initial stage after performing transplantation it is necessary to carry out routine monitoring of such parameters: The ABP, the ECG, the neurologic and visual status, glucose level in blood on an empty stomach, electrolytes (especially potassium), function of a liver and kidneys, parameters of complete blood count test, indicators of coagulation and definition of protein fractions in blood plasma. As well as at use of other immunosuppressive drugs, owing to potential risk of development of malignant changes on skin it is necessary to limit influence of sunshine and ultraviolet radiation, protecting skin clothes and using creams with a high factor of protection. Takrolimus is incompatible with polyvinylchloride. If contents of capsules need to be entered via the nazogastralny probe, the last should not contain polyvinylchloride. Grapefruit juice increases the level of a takrolimus in blood at the expense of inhibition of activity of CYP 3A4. Takrolimus can cause visual and neurologic disturbances. Patients at whom such disturbances developed should not run vehicles or work with mechanisms. This influence can amplify at a concomitant use of the Pro-count with alcohol. Drug can get through a placenta. As safety of use of the Pro-count for pregnant women is not established, it is not necessary to appoint this drug during pregnancy, except for cases when the expected advantage of treatment exceeds potential risk for a fruit. Takrolimus is allocated with breast milk. As it is impossible to exclude negative influence on children of chest age, the women taking the drug have to stop feeding by a breast.
INTERACTIONS: Pharmacokinetic interactions. Takrolimus is substantially metabolized by hepatic microsomal P450 3A4 cytochrome isoenzyme (CYP 3A4). The accompanying intake of the medicines or drugs of plant origin inhibiting or inducing CYP 3A4 can influence metabolism of a takrolimus and lower or increase levels of a takrolimus in blood. Takrolimus influences CYP 3A4-dependent metabolism, combined use of a takrolimus with drugs which are metabolized by CYP in the 3A4-dependent ways, can influence metabolism of these drugs (cortisone, testosterone). Takrolimus considerably contacts proteins of blood plasma. It is necessary to consider possible interactions with other drugs which are vysokoafinny to blood proteins (NPVP, oral anticoagulants or oral antidiabetic drugs). Pharmakodinamichesky interactions. The accompanying reception of a takrolimus with the drugs having nephrotoxic or neurotoxic effects can increase toxicity level (aminoglycosides, giraza inhibitors (sort DNA-topoisomerase II), Vancomycinum, co-trimoxazole, NPVP, gantsiklovir or acyclovir). As treatment takrolimusy can be followed by development of a hyperpotassemia or can strengthen earlier existing hyperpotassemia, it is necessary to avoid excess intake of potassium, use of kaliysberegayushchy diuretics (amiloride, Triamterenum or Spironolactonum). Other interactions. During use of a takrolimus the efficiency of vaccines decreases and it is necessary to avoid administration of live attenuirovanny vaccines. Clinically significant interactions. The drugs marked with an asterisk need changes of doses of a takrolimus practically at all patients. Other drugs which are given below can need correction of a dosage in some cases. The drugs inhibiting CYP 3A4 and increasing levels of a takrolimus in blood: ketokonazol *, flukonazol *, itrakonazol *, Clotrimazolum, vorikonazol *, nifedipine, nikardipin, erythromycin *, klaritromitsin, dzhozamitsin, inhibitors of HIV proteases, danazol, et
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