Адваграф®

General characteristics. Structure:

Active ingredient – такролимус (in the form of a takrolimus of monohydrate) – 0,5 mg, 1 mg or 5 mg; excipients – a gipromelloza, ethyl cellulose, lactoses monohydrate, magnesium stearate; capsule cover: titanium dioxide (Е 171), dye ferrous oxide yellow (Е 172), dye ferrous oxide red (Е 172), gelatin, sodium lauryl sulfate; a text on the capsule (Opacode S-1-15083): glaze of pharmaceutical 45% (shellac solution in ethanol), lecithin (soy), симетикон, dye ferrous oxide red (Е 172), a hypro rod.

Description

Capsules of 0,5 mg:
Solid gelatin capsules No. 5, on a light yellow cover of the capsule the red text of "0,5 mg", on the orange case of the capsule – "647" is put. Contents of capsules – white powder.
Capsules of 1 mg:
Solid gelatin capsules No. 4, on a white cover of the capsule the red text of "1 mg", on the orange case of the capsule – "677" is put. Contents of capsules – white powder.
Capsules of 5 mg:
Solid gelatin capsules of No. in size 0, on a grayish-red cover of the capsule the red text of "5 mg", on the orange case of the capsule – "687" is put. Contents of capsules – white powder.

Pharmacological properties:

Pharmacodynamics. At molecular level effects and intracellular cumulation of a takrolimus are caused by linkng with cytosolic protein (FKBP 12). The FKBP 12-takrolimus complex specifically and competitively inhibits кальциневрин, providing kaltsiyzavisimy blocking of ways of transfer of T-cellular signals and preventing a transcription of a discrete number of limfokinny genes.
Takrolimus – a highly active immunosuppressant. In experiments of in vitro and in vivo такролимус clearly reduced formation of cytotoxic lymphocytes which play a key role in reaction of graft rejection. Takrolimus suppresses formation of lymphokines (Interlaken-2,-3, γ-interferon)))))))))), activation of T-cells, a receptor expression interleykina-2, and also proliferation of V-cells, dependent on T-helperov.

Pharmacokinetics.
Absorption
It is established what in a human body такролимус is quickly absorbed in digestive tract. Advagraf, capsules of the prolonged action – the dosage form providing long absorption of a takrolimus in digestive tract. The average time of achievement of Cmax makes about 2 hours. Absorption of a takrolimus is variable (variability of absorption at adult patients of 6-43%). Bioavailability of a takrolimus at intake in the form of capsules averages 20-25%. Bioavailability, and also speed and extent of absorption of a takrolimus at a concomitant use with food decrease. Character of a zhelchevydeleniye does not influence drug absorption. After achievement of equilibrium concentration of a takrolimus at Advagraf's reception high correlation between AUC and the minimum (C0) concentration of a takrolimus in blood is noted. Therefore monitoring of the minimum (C0) concentration of a takrolimus in blood allows to judge system exposure of drug.
Distribution and elimination
Distribution of a takrolimus in a human body after intravenous administration has two-phase character. In a system blood-groove такролимус well contacts erythrocytes.
Ratio of concentration of a takrolimus in whole blood and plasma ≅ 20:1. The considerable share of a takrolimus of plasma (> 98,8%) is in the state connected with proteins of plasma (a seralbumin, a α-1-kisly glycoprotein).
Takrolimus is widely distributed in an organism. The stationary volume of distribution taking into account concentration in plasma makes about 1 300 l (at healthy people). The same indicator calculated on whole blood is equal on average 47,6 l.
Takrolimus – substance with low clearance. Healthy people have an average general clearance calculated on concentration in whole blood – 2,25 l/hour. At adult patients is after liver transplantation, kidneys and hearts of value of clearance made 4,1 l/hour, 6,7 l/hour and 3,9 l/hour respectively. The low hematocrit and a hypoproteinemia promote increase in untied fraction of a takrolimus, accelerating clearance of a takrolimus. The corticosteroids applied at transplantation can also increase intensity of metabolism and accelerate clearance of a takrolimus.
Elimination half-life of a takrolimus long and changeable. At healthy people the average elimination half-life in whole blood makes about 43 hours.
Metabolism and biotransformation
Takrolimus is actively metabolized in a liver, mainly, by means of P450 CYP3A4 cytochrome. Metabolism of a takrolimus intensively proceeds in an intestines wall. Several metabolites of a takrolimus are identified. In experiments of in vitro it was shown that only one of metabolites has the immunosuppressive activity close to activity of a takrolimus. Other metabolites differed in weak immunosuppressive activity or its absence. In a system blood-groove only one of metabolites of a takrolimus in low concentration is found. Thus, pharmacological activity of drug practically does not depend on metabolites.
Excretion
After intravenous and peroral administration ^{of a 14C-mechenny} takrolimus the main share of radioactivity was found in excrements. About 2% of radioactivity were registered in urine. In urine and excrements about 1% of a takrolimus was defined in an invariable look. Therefore, такролимус before elimination it was almost completely metabolized: the main way of elimination was a bile.

Indications to use:

The prevention and treatment of rejection of allotransplant of a liver, kidney at adult patients.
Treatment of rejection of allotransplant, resistant to the standard modes of immunosuppressive therapy at adult patients.

Route of administration and doses:

Advagraf – a peroral form of a takrolimus for reception once a day. Therapy by Advagraf demands careful control from the personnel having the corresponding qualification and having on hand the necessary equipment. Only the doctors having experience of performing immunosuppressive therapy at patients with transplanted organs can appoint this drug.
Uncontrolled transfer of patients from one drug of a takrolimus on another (including transition from ordinary capsules to the prolonged capsules) is unsafe. It can lead to graft rejection or increase in frequency of side effects, including hypo - or hyper immunosuppression, owing to emergence of clinically significant distinctions in exposure of a takrolimus. The patient should accept one of dosage forms of a takrolimus with observance of the recommended dosing mode. Change of a dosage form or mode of dosing should be carried out only under control of the specialist in the field of transplantology. After transfer it is necessary to carry out careful monitoring of concentration of a takrolimus to blood and to adjust a drug dose for maintenance of system exposure of a takrolimus at the adequate level.
The initial doses given below should be considered only as recommendations. In the initial postoperative stage Advagraf usually apply in combination with other immunodepressants. The dose can vary depending on the mode of immunosuppressive therapy. The choice of a dose of Advagraf has to be based, first of all, on clinical assessment of risk of rejection and individual portability of drug, and also on data of monitoring of level of a takrolimus in blood (see below the section "Recommendations about Monitoring of Therapeutic Concentration of a Takrolimus in Blood").
At emergence of clinical signs of rejection it is necessary to consider a question of need of correction of the mode of immunosuppressive therapy. At the stable patients transferred from the Pro-count (double daily reception) on Advagraf (single daily dose) with the general daily dose 1:1 (мг:мг), system exposure of a takrolimus (the area under pharmacokinetic PFK0-24 scion) at reception Advagrafa was about 10% lower in comparison with the Pro-count. The interrelation between the minimum levels of a takrolimus (C24) and system exposure Advagrafa was same, as at use of the Pro-count. Upon transition (conversion) from the Pro-count on Advagraf it is necessary to measure the minimum levels of a takrolimus as before conversion from one drug on another, and for the next two weeks. At the same time Advagraf's doses should be adjusted for the purpose of achievement of system exposure of a takrolimus similar to the Pro-count.
At patients is after renal transplantation and a liver of de novo PFK0-24 of a takrolimus in the 1st days of use Advagrafa was respectively for 30% and 50% below in comparison with equivalent doses of the Pro-count.
By 4th days the system exposure of a takrolimus estimated on C0 at use of the Pro-count and Advagraf for patients after liver transplantation and a kidney was identical. For the purpose of ensuring adequate exposure of a takrolimus at treatment by Advagraf within the first two weeks after transplantation Regular and careful monitoring of the minimum (C0) concentration of a takrolimus in blood is recommended. As такролимус – substance with low clearance, for achievement of equilibrium concentration after dose adjustment of Advagraf can be required several days.
For patients who cannot accept drug orally directly after transplantation такролимус it can intravenously be entered (Pro-columns 5mgml, a concentrate for infusion) in the dose making about one fifth the recommended peroral dose for this indication.
Route of administration
The peroral daily dose of Advagraf is recommended to be accepted in the morning once a day. Reception of capsules of Advagraf of the prolonged action is carried out right after their extraction from the blister. Patients should be warned about existence in packaging of a moisture absorber (a bag of silica gel) which is not intended for reception. Capsules are recommended to be washed down with liquid (preferably, water). For achievement of the maximum absorption Advagraf is recommended to accept next the heart: in 1 hour or in 2-3 hours after meal. The passed dose should be accepted as soon as possible, it is desirable on the same day; it is not necessary to accept a double dose the next morning.
Duration of administration of drug
For prevention of graft rejection the condition of immunosuppression needs to be supported constantly; therefore, duration of therapy is not limited.

Recommendations about dosing

Transplantation of a kidney
Prevention of graft rejection
Peroral therapy by Advagraf it is necessary to begin with a daily dose 0,20-0,30 mg/kg, once a day in the mornings. Administration of drug should be begun within 24 hours after transplantation.

Transplantation of a liver
Prevention of graft rejection
Peroral therapy by Advagraf it is necessary to begin with a daily dose 0,10-0,20 mg/kg, once a day in the mornings. Administration of drug should be begun in 12-18 hours after transplantation.
Correction of doses during the post-transplant period
Eventually after transplantation of a kidney or a liver of a dose of Advagraf usually reduce. Cancellation of the accompanying immunodepressants, i.e. transition to monotherapy by Advagraf is in certain cases possible. Improvement of a condition of the patient can change pharmacokinetics of a takrolimus and demand additional correction of doses of Advagraf.

Treatment of graft rejection
For the purpose of stopping of graft rejection the following approaches are recommended: increase in a dose of a takrolimus, therapy strengthening by corticosteroids, short courses of therapy моно-/polyclonal antibodies. At emergence of signs of toxicity of a takrolimus (for example, the expressed undesirable reactions), decrease in doses of Advagraf can be required. Information on transition from cyclosporine on Advagraf contains in the section "Conversion (Transition) from Cyclosporine on Advagraf".
Transplantation of a kidney and liver
Upon transition from other immunodepressants on Advagraf treatment should be begun with the initial peroral doses described above in the sections "Prevention of Graft Rejection" at transplantation of a kidney and liver.
Transplantation of heart
Upon transition to therapy by Advagraf at adult patients, the initial peroral daily dose of drug makes 0,15 mg/kg, once a day in the mornings.
Change of other bodies
Clinical experience of use of Advagraf for treatment of patients after change of a lung, a pancreas, intestines is absent. However такролимус (Pro-count) it is applied at patients with lung transplants in an initial peroral dose of 0,10-0,15 mg/kg/days, after transplantation of a pancreas in an initial peroral dose of 0,2 mg/kg/days, after transplantation of intestines in an initial peroral dose of 0,3 mg/kg/days.

Conversion (transition) from cyclosporine on Advagraf
Upon transition from cyclosporine on Advagraf it is necessary to be careful. Treatment by Advagraf is recommended to be begun after definition of concentration of cyclosporine in blood and assessment of a clinical condition of the patient. Conversion should be postponed in the presence of the increased cyclosporine levels to blood. In practice therapy takrolimusy begins in 12-24 hours after the cyclosporine reception termination. After transition it is recommended to control cyclosporine levels in blood as delay of clearance of cyclosporine is possible.

Conversion (transition) from the Pro-count on Advagraf
If patients after allotransplantation, the accepting Pro-columns twice a day, it is necessary to transfer to Advagraf's reception once a day, the ratio of daily doses during transition has to make 1:1 (мг:мг). Advagraf is recommended to accept in the mornings. After transition on Advagraf it is necessary to control the minimum (C0) concentration of a takrolimus in blood and to carry out dose adjustment of drug for maintenance of system exposure of a takrolimus at the previous level.

Correction of doses at separate categories of patients
Patients with hepatic dysfunction
At patients with heavy hepatic dysfunction for maintenance of the minimum (C0) concentration of a takrolimus in blood within the recommended therapeutic range Advagraf dose decline can be required.
Patients with renal dysfunction
As renal function does not influence pharmacokinetics of a takrolimus, need for correction of doses is absent. However in connection with the nephrotoxic potential of a takrolimus it is recommended to monitorirovat carefully renal function (including definition of concentration of serumal creatinine, calculation of clearance of creatinine and control over amount of the emitted urine).
Race
At black patients for achievement of similar minimum (C0) concentration of a takrolimus in blood higher doses of drug, than at patients of white race can be required.
Floor
Data that different doses of drug for achievement of equal minimum (C0) concentration of a takrolimus in blood are required for men and women are absent.
Elderly patients
Data that special doses of Advagraf are required for elderly patients no.

Recommendations about monitoring of therapeutic concentration of a takrolimus in blood

The choice of doses has to be based on clinical assessment of individual risk of rejection and portability of drug, and also on data of monitoring of therapeutic level of a takrolimus in blood.
Several methods of definition of concentration of a takrolimus in whole blood are applied to the choice of an optimum dose. Comparison of the results of monitoring published in literature with results of monitoring in separate clinic needs to be carried out taking into account the applied method of definition of concentration of a takrolimus of blood. In modern clinical practice levels of a takrolimus in blood are controlled preferential by means of immunoanalysis methods.
Correlation between the minimum (C0, C24) concentration and system exposure (AUC0-24) of a takrolimus in blood at use of both drugs, Advagraf and the Pro-count, is identical.
During the post-transplant period careful monitoring of the minimum (C0, C24) concentration of a takrolimus in blood is necessary. The minimum concentration of Advagraf in blood should be defined approximately in 24 hours after administration of drug, before reception of the following dose. In the first two weeks after transplantation it is recommended to carry out more frequent monitoring of the minimum concentration, then in the period of a maintenance therapy periodic monitoring is carried out. Therapeutic level of a takrolimus in blood should be controlled with special care after transition from the Pro-count on Advagraf, at correction of doses of drugs, at modification of the mode of immunosuppressive therapy or at simultaneous use of drugs which can cause change of concentration of a takrolimus in blood (see the sections "Conversion (Transition) From Cyclosporine on Advagraf.", "Conversion (Transition) from the Pro-count on Advagraf." and "Interaction with Other Medicines"). Frequency of monitoring of level of drug in blood is defined by clinical need. As Advagraf – drug with low clearance, for achievement of equilibrium concentration of a takrolimus in blood after dose adjustment of Advagraf can be required several days.
According to data of clinical trials, in most cases treatment is successful at therapeutic levels of a takrolimus in blood not higher than 20 ng/ml. At interpretation of data on therapeutic concentration of a takrolimus in blood it is necessary to take a clinical condition of the patient into account.
According to the available data, in the initial post-transplant stage at patients after transplantation of a liver the therapeutic level of drug in blood is in range of 5-20 ng/ml, and after renal transplantation or heart – 10-20 ng/ml. During the supporting immunosuppressive therapy at patients after liver transplantation, a kidney or hearts of concentration of drug in blood usually are in limits of 5-15 ng/ml.

Features of use:

Experience of treatment of the patients who are not belonging to white race and also patients with high immunological risk (i.e. at repeated transplantation, a high caption of panel reactive antibodies [PRA]) is limited. Clinical data on Advagraf's use at acute rejection, refractory to therapy by other immunodepressants at adult patients, no.
There are no clinical data on Advagraf's use for the purpose of prevention of graft rejection at heart transplantation and at children's age now.
In the initial post-transplant stage it is necessary to carry out regular monitoring of the following parameters: arterial pressure, ECG, neurologic status and condition of sight, glycemia level on an empty stomach, concentration of electrolytes (especially potassium), indicators of hepatic and renal function, hematologic indicators, koagulogramma, proteinemia level. In the presence of clinically significant changes, correction of immunosuppressive therapy is necessary.
At Advagraf's use it is necessary to avoid purpose of the vegetable drugs containing a St. John's Wort (Hypericum perforatum) and also other vegetable means which can cause decrease (change) in concentration of a takrolimus in blood and exert adverse impact on clinical effect of Advagraf.
At diarrhea levels of a takrolimus in blood can change considerably; at emergence of diarrhea careful monitoring of concentration of a takrolimus in blood is necessary.
It is necessary to avoid simultaneous use of cyclosporine and a takrolimus, and also to be careful at treatment takrolimusy patients who received cyclosporine earlier (see the section "Conversion (Transition) from Cyclosporine on Advagraf.").
Cases of a hypertrophy of ventricles or hypertrophy of partitions of heart about which it was reported as about a cardiomyopathy seldom, but were observed at patients, the accepting Pro-columns and therefore are possible at treatment by Advagraf. In most cases the hypertrophy of a myocardium was reversible and was observed at the concentration (C0) of a takrolimus in blood exceeding recommended. Treat other factors increasing risk of this undesirable phenomenon: existence of the previous heart disease, use of corticosteroids, arterial hypertension, renal and hepatic dysfunction, infections, a hypervolemia, hypostases. The patients having high risk and receiving intensive immunosuppressive care before and after transplantation (in 3 and 9-12 months) need to carry out echocardiographic and an ECG control. If anomalies come to light, it is necessary to consider a question of a dose decline of Advagraf or replacement of drug by other immunosuppressant.
Takrolimus can cause lengthening of an interval of QT, at the same time disturbances of a heart rhythm like "pirouette" (bidirectional spindle-shaped ventricular tachycardia) were not observed. At treatment of patients with the diagnosed inborn syndrome of the extended interval of QT or suspicion on a similar state it is necessary to observe extra care.
At the patients treated takrolimusy development of post-transplant limfoproliferativny diseases (PTLZ) associated with Epstein's virus - Barrel is possible. At simultaneous use of drug with anti-lymphocytic antibodies the risk of PTLZ increases. Also patients have data on increase in risk of PTLZ with the revealed kapsidny antigen of a virus of Epstein-Barre Poetomu before Advagraf's appointment for this group of patients it is necessary to conduct a serological research on availability of kapsidny antigen of a virus of Epstein - Barrel. In the course of treatment it is recommended to carry out careful monitoring on Epstein-Barre's virus by means of the polymerase chain reaction (PCR). Positive PTsR on Epstein-Barre's virus can remain within months and in itself is not the certificate of PTLZ or lymphoma.
At the patients receiving immunosuppressive therapy, including Advagraf, the risk of the opportunistic infections (caused by bacteria, mushrooms, viruses, the elementary) is increased. Among these infections the nephropathy associated with the VK-virus, and also the progressing multifocal leukoencephalopathy (PML) associated with a JC virus is noted. Such infections are often connected with deep suppression of immune system and can lead to heavy or fatal outcomes that it is necessary to take into account when carrying out the differential diagnosis at the patients having signs of disturbance of renal function or neurologic symptoms against the background of immunosuppressive therapy.
Immunosuppressive therapy increases risk of malignant new growths. It is recommended to limit insolation and ultra-violet radiation, to wear the corresponding clothes, to use sun-protection means with a high factor of protection.
The risk of development of secondary cancer is unknown.
There are messages on emergence of a syndrome of reversible back encephalopathy against the background of therapy takrolimusy. If the patient accepting такролимус has symptoms characteristic of a syndrome of reversible back encephalopathy: a headache, mental disturbances, spasms and visual disturbances, it is necessary to carry out a magnetic and resonant tomography. At confirmation of the diagnosis it is necessary to exercise adequate control over arterial pressure and spasms, and also to immediately stop system introduction of a takrolimus. In case of acceptance of the specified measures this state is completely reversible at most of patients.
As Advagraf's capsules of the prolonged action contain lactose, it is necessary to observe extra care at purpose of drug to patients with the rare hereditary diseases connected with intolerance of a galactose, insufficiency of lactase of Lapp or glyukozo-galaktozny malabsorption.

Use at pregnancy and in the period of a lactation
Pregnancy
Results of the preclinical trials and researches conducted in public show that drug can get through a placenta. There are messages on premature births (<37 weeks), and also cases of spontaneously resolved hyperpotassemia for newborns (8 of 111 (7,2%) newborns). As safety of use of a takrolimus for pregnant women is not established sufficiently, drug is accepted during pregnancy only in case of lack of safer alternative and only when benefited from treatment justifies potential risk for a fruit. For the purpose of identification of potential undesirable reactions of a takrolimus it is recommended to control a condition of newborns whose mothers during pregnancy accepted такролимус (in particular, to pay attention to renal function).
Lactation period
According to clinical experience, такролимус gets into breast milk. As it is not possible to exclude an adverse effect of a takrolimus on the newborn, the women accepting Advagraf should refrain from feeding by a breast.

Influence on ability to manage vehicles and to work with mechanisms
Takrolimus can cause visual and neurologic frustration, especially in Advagraf's combination to alcohol.

Side effects:

Due to the features of a basic disease and a large amount of the medicines used at the same time after transplantation, precisely it is difficult to establish a profile of the undesirable phenomena of immunodepressants.
Many of the undesirable phenomena given below are reversible and/or decrease at a dose decline. Within each frequency group the undesirable phenomena are presented as the decreasing gravity. The undesirable phenomena classified by bodies and systems are listed below as the decreasing identification frequency: very frequent (> 1/10), frequent (from> 1/100 to <1/10), infrequent (from> 1/1000 to <1/100), rare (from> 1/10 000 to <1/1 000), very rare (<1/10 000), unknown (for who establishment of frequency are not enough data).
Heart
frequent: ischemic coronary frustration, tachycardia
infrequent: ventricular arrhythmias and cardiac standstill, heart failure, cardiomyopathy, hypertrophy of ventricles, supraventricular arrhythmias, tachycardia, abnormal indicators of an ECG, disturbance of a rhythm and heart rate and pulse
rare: pericardiac exudate
very rare: abnormal indicators of an ekhokardiogramma
Blood and lymphatic system
frequent: anemia, leukopenia, thrombocytopenia, leukocytosis
infrequent: coagulopathies, deviations in koagulogramma indicators, a pancytopenia, a neutropenia
rare: trombotichesky Werlhof's disease, prothrombinopenia
Nervous system
very frequent: tremor, headache
frequent: epileptoidny attacks, disturbances of consciousness, paresthesia and dizesteziya, peripheral neuropathies, dizziness, disturbance of the letter, frustration of a nervous system
infrequent: a coma, hemorrhages in the central nervous system and disturbances of cerebral circulation, paralysis and paresis, encephalopathy, disturbances of the speech and an articulation, amnesia
rare: increase in a muscle tone
very rare: myasthenia
Organ of sight
frequent: sight illegibility, photophobia, diseases of eyes
infrequent: cataract
rare: blindness
Acoustic organ and balances
frequent: noise (ring) in ears
infrequent: decrease in hearing
rare: neurosensory deafness
very rare: hearing disorder
Respiratory system and mediastinum
frequent: asthma, pulmonary parenchymatous frustration, pleural exudate, pharyngitis, cough, nose congestion, rhinitis
infrequent: respiratory insufficiency, frustration from respiratory tracts, asthma
rare: acute respiratory distress syndrome
Gastrointestinal frustration
very frequent: diarrhea, nausea
frequent: inflammatory diseases of digestive tract, gastrointestinal ulcers and perforations, gastrointestinal bleedings, stomatitis and an ulceration of a mucous membrane of an oral cavity, ascites, vomiting, gastrointestinal and abdominal pain, dyspepsia, locks, a meteorism, feelings of swelling and a raspiraniye in a stomach, a liquid chair, symptoms of disturbances from digestive tract
infrequent: paralytic intestinal impassability (paralytic Ilheus), peritonitis, acute and chronic pancreatitis, the increase in level of amylase in blood, a gastroesophageal reflux disease broken evakuatorny function of a stomach
rare: субилеус, pancreatic pseudocysts
Kidneys and uric ways
very frequent: disturbance of renal function
frequent: a renal failure, an acute renal failure, an oliguria, an acute canalicular necrosis, a toxic nephropathy, an uric syndrome, frustration from a bladder and an urethra
infrequent: anury, hemolitic uraemic syndrome
very rare: nephropathy, hemorrhagic cystitis
Skin and hypodermic cellulose
frequent: itch, rash, alopecia, acne, hyperhidrosis
infrequent: dermatitis, photosensitization
rare: toxic epidermal necrolysis (Lyell's disease)
very rare: Stephens-Johnson's syndrome
Musculoskeletal system and connecting fabric
frequent: arthralgia, muscular spasms, extremity pain, dorsodynia
infrequent: joint frustration
Endocrine system
rare: hirsutism
Metabolism and food
very frequent: hyperglycemia, diabetes mellitus, hyperpotassemia
frequent: hypomagnesiemia, hypophosphatemia, hypopotassemia, hypocalcemia, hyponatremia, hypervolemia, hyperuricemia, loss of appetite, anorexia, metabolic acidosis, lipidemia, hypercholesterolemia, gipertriglitseridemiya, electrolytic disturbances
infrequent: dehydration, hypoproteinemia, hyperphosphatemia, hypoglycemia
Immune system (infections and invasions)
Against the background of therapy takrolimusy, as well as other immunodepressants, the risk of local and generalized infectious diseases increases (virus, bacterial, fungal, protozoan). The course of earlier diagnosed infectious diseases can worsen. Cases of the nephropathy associated with the VK-virus and also the progressing multifocal leukoencephalopathy (PML) associated with a JC virus were observed against the background of immunosuppressive therapy, including therapy by Advagraf.
Injuries, poisonings, complications of procedures
frequent: primary dysfunction of a transplant
The high-quality, malignant and not identified new growths
The patients receiving immunosuppressive therapy have higher risk of malignant tumors. At use of a takrolimus emergence of both high-quality, and malignant new growths, including Epstein-Barre's (EBV) virus – the associated limfoproliferativny diseases and a carcinoma cutaneum is noted.
Vascular system
very frequent: arterial hypertension
frequent: bleeding, tromboembolic and ischemic episodes, disturbance of peripheric circulation, arterial hypotension
infrequent: heart attack, deep vein thrombosis of extremities, shock
General frustration and complications
frequent: an adynamy, feverish states, hypostases, pain and discomfort, increase in level of an alkaline phosphatase in blood, increase in body weight, disturbance of perception of body temperature
atypical: multiorgan insufficiency, a grippopodobny syndrome, disturbances of perception of ambient temperature, feeling of squeezing in a breast, feeling of alarm, deterioration in health, increase in level of a lactate dehydrogenase in blood, decrease in body weight
rare: thirst, loss of balance (falling), feeling of constraint in a thorax, difficulties of the movement
very rare: increase in mass of fatty tissue
Immune system (allergic reactions)
At the patients accepting такролимус allergic and anaphylactic reactions were observed.
Liver and bilious ways
frequent: increase in level of liver enzymes, abnormal liver functions, cholestasia and jaundice, defeat of cells of a liver and hepatitis, cholangitis
rare: the thrombosis of a hepatic artery obliterating an endophlebitis of hepatic veins
very rare: liver failure, stenosis of bilious channels
Reproductive system and mammary glands
infrequent: dysmenorrhea and uterine bleeding
Fertility
The negative influence of a takrolimus on male fertility which is expressed in reduction of number and mobility of spermatozoa is established at rats.
Mental sphere
very often: sleeplessness
often: uneasiness, confusion of consciousness and a disorientation, a depression, the suppressed mood, emotional frustration, nightmares, hallucinations, mental disorders
infrequent: psychotic frustration

Interaction with other medicines:

Metabolic interactions
After oral administration такролимус is exposed to metabolism in system of intestinal CYP3A4 cytochrome. The concomitant use of drugs or officinal herbs with the action established inhibiting or inducing on CYP3A4 can raise or lower respectively concentration of a takrolimus in blood. Therefore for maintenance of adequate and constant exposure of a takrolimus it is recommended to control concentration of a takrolimus in blood and, if necessary, to adjust Advagraf's dose.

Metabolism inhibitors
On the basis of clinical experience it was established that in blood the following drugs can significantly increase concentration of a takrolimus:
antifungal means (кетоконазол, флуконазол, итраконазол, вориконазол), makrolidny antibiotics (erythromycin), HIV inhibitors of proteases (ритонавир). At purpose of these drugs with takrolimusy decrease in doses of Advagraf can be required. Pharmacokinetic researches showed that increase in level of a takrolimus in blood is, first of all, a consequence of increase in peroral bioavailability of the drug caused by inhibition of intestinal metabolism of a takrolimus. Suppression of hepatic metabolism of a takrolimus plays a supporting role.
Less expressed medicinal interaction was observed at simultaneous use of a takrolimus with Clotrimazolum, klaritromitsiny, dzhozamitsiny, nifedipine, nikardipiny, diltiazem, verapamil, danazoly, ethinylestradiol, omeprazoly and nefazodony.
In the researches in vitro it was shown that potential inhibitors of metabolism of a takrolimus are the following substances: Bromocriptinum, a cortisone, dapsone, ergotamine, гестоден, lidocaine, Mephenytoinum, Miconazolum, midazolam, нилвадипин, норэтинодрон, quinidine, Tamoxifenum, (triatsetit) Oleandomycinum.
Also it is recommended to avoid some grapefruit juice in connection with a possibility of increase in level of a takrolimus in blood. Lansoprazol and cyclosporine can potentially inhibit CYP3A4 - the mediated metabolism of a takrolimus and to increase its concentration in blood.

Metabolism inductors
On the basis of clinical experience it was established that in blood the following drugs can significantly reduce concentration of a takrolimus: rifampicin, Phenytoinum, St. John's Wort (Hypericum perforatum). At purpose of these drugs with takrolimusy increase in doses of Advagraf can be required.
Clinically significant interactions were observed with phenobarbital.
Corticosteroids in maintenance doses usually reduce concentration of a takrolimus in blood. The high doses of Prednisolonum or Methylprednisolonum which are applied to treatment of acute rejection can increase or reduce the level of a takrolimus in blood.
Carbamazepine, metamizol and isoniazid can reduce concentration of a takrolimus in blood.

Influence of a takrolimus on metabolism of other medicines
Takrolimus inhibits CYP3A4 and at a concomitant use can exert impact on the drugs which are metabolized in the CYP3A4 system. The cyclosporine elimination half-life at simultaneous use with takrolimusy increases. Also the synergy/additive nephrotoxic effects can be observed. For these reasons the concomitant use of cyclosporine and a takrolimus is not recommended, and at purpose of a takrolimus to patients who accepted cyclosporine earlier, it is necessary to be careful.
Takrolimus increases Phenytoinum level in blood.
As такролимус can reduce clearance of hormonal contraceptives, it is important to be careful at the choice of contraceptives.
Data on interaction of a takrolimus with statines are limited. Clinical observations allow to draw a conclusion that at a concomitant use with takrolimusy the pharmacokinetics of statines does not change.
Pilot studies on animals showed that такролимус the clearance is potentially capable to lower and to increase an elimination half-life of phenobarbital and antipyrine.

Other potential interactions increasing system exposure of a takrolimus
Pro-kinetic means (Metoclopramidum, цизаприд). Cimetidinum. Hydroxide of magnesium and aluminum.

Other potentially adverse medicinal interactions
Simultaneous use of a takrolimus with the drugs possessing nefro-or a neurotoxicity (for example, aminoglycosides, giraza inhibitors, Vancomycinum, co-trimoxazole, non-steroidal anti-inflammatory drugs, ганцикловир, an acyclovir) can promote strengthening of these effects.
As a result of combined use of a takrolimus with Amphotericinum In and an ibuprofen nephrotoxicity strengthening was observed.
As такролимус can promote development or strengthen a hyperpotassemia, it is necessary to avoid use of high doses of potassium or kaliysberegayushchy diuretics (amiloride, Triamterenum, Spironolactonum).
Immunodepressants can change reaction of an organism to vaccination: vaccination during treatment takrolimusy can be less effective. It is necessary to avoid use of live attenuated vaccines.

Linkng with proteins
Takrolimus actively contacts proteins of a blood plasma. It is necessary to consider possible competitive interaction of a takrolimus with the drugs having high affinity to proteins of a blood plasma (non-steroidal anti-inflammatory drugs, peroral anticoagulants, peroral antidiabetic means).

Incompatibility
Takrolimus is incompatible with polyvinylchloride (PVC). Test tubes, syringes and other equipment used at preparation of suspension from Advagraf's capsules should not contain PVC.

Contraindications:

Hypersensitivity to a takrolimus, other macroleads or any of excipients.

Overdose:

Data on overdose are limited. It was reported about several episodes of accidental overdoses at the patients accepting такролимус. Symptoms included a tremor, a headache, nausea, vomiting, infections, urticaria, a lethargic condition, the increased maintenance of an urea nitrogen in blood, serumal creatinine and alaninaminotranspherase.
Now antidotes to a takrolimus do not exist. In case of overdose it is necessary to take standard measures and to carry out a symptomatic treatment.
Considering the high molecular weight of a takrolimus, bad solubility in water and the expressed linkng with erythrocytes and proteins of plasma, dialysis is inefficient. At certain patients with very high concentration of a takrolimus in blood haemo filtering or a diafiltration were effective. In cases of peroral overdose the gastric lavage and/or use of adsorbents (for example, absorbent carbon) can be effective if to take these measures soon after administration of drug.

Storage conditions:

To store in original packaging at a temperature not above 25 °C in the place, unavailable to children. A period of validity - 3 years. After opening of an aluminum package: 1 year.
Drug should not be used after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Capsules of the prolonged action of 0,5 mg, 1 mg, 5 mg. On 10 capsules in the blister from PVC / aluminum foil, on 5 blisters in the soldered aluminum package together with a bag of silica gel.
On 1 soldered aluminum package together with the application instruction in a cardboard pack.