Rapamun

General characteristics. Structure:

Active veshchestvo:platsebo-kernel of a tablet pressed: lactoses monohydrate – 86,4 mg; a macrogoal-8000 – 28,8 mg; magnesium stearate – 0,600 mg; talc – 4,20 mg; Shellac Layer: a macrogoal-20000 – 0,300 mg; glyceryl monooleate (60%) – 0,150 mg; glaze pharmaceutical (shellac solution No. 4) – 5,62 mg (in terms of dry matter – 1,956 mg); calcium sulfate – 10,7 mg; Exicipient Layer: cellulose microcrystallic – 7,32 mg; sucrose – 97,6 mg; titanium dioxide – 0,100 mg; Layer of an active filler: a sirolimusa a nanosystem of disperse 150 mg/g (сиролимус 100% (active agent) – 1,02 mg; half-oxameasures-188 – 0,51 mg; sucrose – 99,20 mg; cellulose microcrystallic – 0,714 mg; povidon-K29-32 – 0,510 mg; alpha tocopherol acetate – 0,051 mg; The Cover painted: sucrose – 19,0 mg; titanium dioxide – 0,923 mg; povidon-K29-32 – 0,077 mg; Polish: wax of karnaubskiya – 0,079 mg; Marking: ink red – опакод S-1-15095 [shellac solution ~ 45% (contains 20% of esters) in ethanol, dye ferrous oxide red (E172), isopropanol, butanol, propylene glycol, ammonia water, симетикон] – 0,200 mg.

Pharmacological properties:

Pharmacodynamics. Sirolimus inhibits activation of T lymphocytes due to blocking calcium - mediated and calcium - independent intracellular signal transmission. Data of researches demonstrate that the mechanism of action of a sirolimus differs from the mechanism of effect of cyclosporine, a takrolimus and other immunodepressants. According to experimental data, сиролимус communicates with specific cytosolic protein - the immunoeagle owl who is FK connecting by protein-12 (FKPB-12), and the FKPB-12-sirolimus complex suppresses enzyme activation - kinases which is a target for Rapamitsin in an organism of mammals (mTOR-mammalian Target of Rapamycin) and has basic value for development of a cellular cycle. The inhibition of mTOR leads to blocking of several specific ways on which there is a signal transmission. Finally the activation of lymphocytes leading to an immunosuppression is inhibited. 

Pharmacokinetics. The most part of information stated in this section is received from experience of use of solution for intake. Information relating directly to a dosage form in the form of tablets, coated is located regarding "Tablet".
Solution for intake
After intake Rapamun (сиролимус) is quickly soaked up; at the same time peak concentration is reached approximately in one hour after a single dose by healthy people, and approximately in two hours after repeated reception by patients in a stable clinical state after allogenic transplantation of a kidney. System bioavailability of Rapamun at a concomitant use with cyclosporine equals about 14%. At the subsequent reception average concentration of a sirolimus in blood increases approximately by 3 times. The elimination half-life (t1/2) at repeated oral administration of drug by patients in a stable clinical state after renal transplantation made 62 16 hours, and average equilibrium concentration were reached in 5 - 7 days. The coefficient reflecting a concentration ratio in blood to concentration in plasma (K/P) equals 36. It demonstrates to what сиролимус substantially collects in uniform elements of blood.
Sirolimus is substrate both for an isoenzyme of system of P450 IIIA4 cytochrome (CYP3A4), and for the R-glycoprotein. Sirolimus is exposed to extensive metabolism by means of O-demethylation and/or a hydroxylation. In blood seven main metabolites, including a hydroxyl - dimetil-, and hydroxydimethyl derivatives are defined. Nevertheless, in blood of the person сиролимус is the main component of drug which more than for 90% defines an immunodepressive effect of Rapamun. After a single dose [14C] - a sirolimus healthy volunteers the main part (91,1%) of drug, marked a radioisotope, was found in Calais, and only a small part (2,2%) was excreted with urine.
At the children who are on dialysis (with reduction in the rate of glomerular filtering for 30-50%) 5-11 years and 12-18 years were celebrated that the average normalized on body weight, the clearance relation to filtering (CL/F) is higher in a younger age group (580 ml/hour/kg), in comparison with the senior age group (450 ml/hour/kg) whereas at adults the corresponding value makes 287 ml/hour/kg. Within each age group variability of this indicator over a wide range is noted.
At patients with an abnormal liver function from easy (degree And or In on Child-Pugh scale) average values of the area under a curve "concentration time" (AUC) and t1/2 of a sirolimus were increased to moderate severity, respectively, for 61 and 43%, and average CL/F value is reduced by 33% in comparison with healthy examinees. At patients with the expressed abnormal liver function (degree With on Child-Pugh classification) average AUC values and t1/2 of a sirolimus were increased, respectively, for 210% and 170%, and average CL/F value is reduced by 67% in comparison with healthy examinees. Longer t1/2 of drug as a result of an abnormal liver function led to delay of achievement of its equilibrium state in an organism.
In group of patients with various function of kidneys – from normal to completely absent (patients on a hemodialysis) pharmacokinetic parameters of a sirolimus were similar.
Tablets
At healthy volunteers the average size of bioavailability of a sirolimus after purpose of a single dose in the form of tablets is about 27% higher than the corresponding indicator after solution reception; average maximum concentration (Smaks.) 35% lower, and average time of achievement of the maximum concentration (tmaks.) – 82% higher. After achievement of an equilibrium condition of a sirolimus recipients of renal transplants in bioavailability had less expressed distinction. In a randomized research with participation of 477 patients therapeutic equivalence of two dosage forms was shown. At transfer of patients from solution for intake it is recommended to appoint a former dose to tablets and to control the minimum concentration of a sirolimus in blood in 1 - 2 weeks to be convinced that it remains in the recommended limits.
At 24 healthy volunteers receiving under observation of a tablet of Rapamun together with food with the high content of fat increase in Smaks was noted., tmaks. and AUC, respectively, for 65, 32 and 23%. To minimize fluctuations, Rapamun's pill should be taken always either together with food, or without food. It is not necessary to use grapefruit juice which influences CYP3A4 the mediated metabolism of a sirolimus.
Initial therapy (within 2 - 3 months after transplantation): At most of patients at whom treatment with Rapamun's tablets is begun with a saturation dose (6 mg) with the subsequent transition to a maintenance dose of 2 mg once a day the minimum concentration of a sirolimus in blood quickly reach the equilibrium concentration corresponding to the set interval (from 4 to 12 ng/ml according to a stratographic analysis).
According to monitoring of all patients during receiving cyclosporine as the accompanying therapy, average concentration of a sirolimus in blood (a hromatografichesky method), made 8,6±3,0 ng/ml at the size of a daily dose of 2,1±0,70 mg.
Maintenance therapy: in 3-12 months after cyclosporine cancellation indicators of the minimum level of a sirolimus in blood (a hromatografichesky method) made 19±4,1 ng/ml against the background of reception of daily doses of 8,2±4,2 mg. Thus, the dose of a sirolimus was about 4 times higher than settlement.

Indications to use:

Rapamun is intended for prevention of graft rejection at adult patients with low or moderate immunological risk after transplantation of a kidney. Rapamun initially in a combination with glucocorticosteroids and a microemulsion of cyclosporine within the first 2-3 months after transplantation is recommended to appoint. Therapy by Rapamun can be continued in the form of a maintenance therapy together with glucocorticosteroids only if cyclosporine is gradually cancelled.

Route of administration and doses:

Rapamun is intended only for intake.
It is not recommended to break integrity of tablets before their proglatyvaniye because bioavailability of drug after crush, chewing or the razlamyvaniya of tablets was not studied.
Rapamun it is necessary to accept constantly either along with meal, or between meals.
Therapy has to be carried out under observation of the doctor-transplantologist.
Adults
Initial therapy (within 2-3 months after transplantation): at the usual mode of reception, as soon as possible after transplantation, inside once appoint a shock dose of Rapamun, equal 6 mg, with the subsequent purpose of a dose in 2 mg once a day. Afterwards Rapamun's dose is selected individually so that the minimum concentration in blood made from 4 to 12 ng/ml (a hromatografichesky method). Treatment by Rapamun is continued against the background of a simultaneous gradual dose decline of glucocorticosteroids and a microemulsion of cyclosporine.
Within the first 2-3 months after transplantation it is recommended to maintain the minimum concentration of cyclosporine within 150-400 ng/ml (an immune method of definition of concentration).
Maintenance therapy: in 4-8 weeks after an initiation of treatment cyclosporine its dose should be reduced gradually up to full drug withdrawal, and to select Rapamun's dose so that the minimum concentration in blood made from 12 to 20 ng/ml (a hromatografichesky method). Rapamun it is necessary to accept together with glucocorticosteroids. To patients at whom cancellation of cyclosporine was unsuccessful or it is impossible, duration of joint therapy by cyclosporine and Rapamun should not make more than 3 months. In clinically justified situations such patients should cancel Rapamun and to appoint the alternative mode of an immunosuppression.
Data for use of a sirolimus for patients of negroid race are not enough.
Elderly patients (65 years are more senior):
Experience of use of Rapamun for patients is more senior than 65 years is insufficient to define whether there are distinctions in the response to therapy between patients of this age group and younger. At 35 patients 65 years after renal transplantation are more senior the minimum concentration of a sirolimus did not differ from the corresponding concentration at 822 patients from 18 to 65 years. The results received at purpose of tablets of Rapamun to 12 patients aged is more senior than 65 years after transplantation of kidneys, also corresponded to the results received for adult patients (n=167) aged from 18 up to 65 years.
Use for patients with disturbances of functions of kidneys: patients have no need for change of a dose with renal failures.
Use for patients with disturbances of functions of a liver: at the expressed abnormal liver function the maintenance dose of Rapamun is recommended to be reduced approximately twice in connection with the slowed-down clearance of drug. The shock dose should not be changed.
Monitoring of therapeutic concentration of medicine: At most of the patients receiving 2 mg of Rapamun in 4 hours after cyclosporine, the minimum concentration of a sirolimus in blood corresponded to the set interval from 4 to 12 ng/ml (according to a stratographic analysis).
Optimum therapy demands monitoring of therapeutic concentration of medicine from all patients. Concentration of a sirolimus in blood needs to be controlled especially carefully at the following groups of patients: (1) patients with an abnormal liver function; (2) during co-administration of inductors or inhibitors of system of CYP3A4 cytochrome, and also after the end of their reception (see the section "Medicinal and Other Types of Interactions"); and/or (3) in case of a sharp dose decline or cancellation of cyclosporine as these groups of patients with the greatest probability will require modification of a dose.
To minimize fluctuations of concentration of a sirolimus, Rapamun it is necessary to accept through constant intervals of time in relation to cyclosporine, namely in 4 hours after cyclosporine reception. In an optimum case selection of a dose of Rapamun has to be based on more, than the single measurement of the minimum concentration executed not earlier than in 5 days after the last change of a dose. After an initiation of treatment the patient can continue by Rapamun's solution therapy by Rapamun in tablets at exact preservation of a dose. After transfer of the patient into other dosage form or other mode of dosing it is recommended to measure the minimum concentration of a sirolimus within 1 - 2 weeks.
After cancellation of cyclosporine it is recommended to maintain the minimum concentration of a sirolimus in blood at the level of 12-20 ng/ml (a hromatografichesky method). Cyclosporine inhibits metabolism of a sirolimus therefore if Rapamun's dose is not increased, concentration of a sirolimus after cancellation of cyclosporine will decrease. On average, Rapamun's dose has to be 4 times higher taking into account lack of pharmacokinetic interaction (2-fold increase) and the increased need for an immunosuppression for lack of cyclosporine (2-fold increase). Speed of increase in a dose Rapamuna has to correspond to cyclosporine cancellation speed.
In need of correction of a dose at a maintenance therapy (after cyclosporine cancellation), it can be carried out at most of patients on the following formula: new dose of Rapamun = current dose x (desirable concentration / current concentration). The shock dose should be applied in addition to a maintenance dose if it is required to increase the minimum concentration of a sirolimus considerably: a shock dose of Rapamun = 3 x (a new maintenance dose - the current maintenance dose). The maximum day dose of Rapamun should not exceed 40 mg. If the calculated day dose exceeds 40 mg because of a shock dose, it is longer necessary to accept a shock dose 2 days. Definition of the minimum concentration of a sirolimus should be carried out, at least, in 3-4 days after purpose of a shock dose.
After change of a dose or reception of a shock dose of Rapamun at patients with a heavy liver failure in connection with delay of achievement of an equilibrium state control of level of drug it is necessary to spend each 5-7 days to blood until 3 consecutive definitions of concentration of a sirolimus do not confirm achievement of stable level.
Calculation of 24-hour minimum concentration of a sirolimus is based on results of hromatografichesky methods. For measurement of concentration of a sirolimus in blood used various approaches. Now concentration of a sirolimus are measured in blood by both hromatografichesky, and immunoenzyme methods. The sizes of concentration received by these methods are not interchanged. Using immunoenzymatic systems, it is always necessary to follow recommendations of the producer to correlate the received values with that, the received standard hromatografichesky methods. All concentration of a sirolimus given in this document were measured by methods of a chromatography or counted in the corresponding equivalent sizes. For definition of desirable minimum concentration of a sirolimus it is necessary to carry out adjustment according to the used methods.
Monitoring of therapeutic concentration of medicine should not be the only reference point at selection of a dose of a sirolimus. Special attention should be paid to clinical symptoms, results of a histologic research and datas of laboratory.

Features of use:

So far enough data on Rapamun's use for patients with high immunological risk are not obtained.
There is a research experience to destination of a sirolimus jointly with the following medicines: cyclosporine, Azathioprinum, mikofenolaty mofetit, glucocorticosteroids and cytotoxic antibodies. Rapamun's combinations with other immunodepressive drugs are studied insufficiently.
Purpose of a sirolimus, mikofenolat of a mofetil and glucocorticosteroids in a combination with antibodies to Interlaken (IL) is not recommended to-2 receptors at change of a renal transplant of de novo.
Immunodepressants can exert impact on efficiency of vaccination. During treatment by immunodepressants, including Rapamun, vaccination can be less effective. During treatment by Rapamun it is necessary to avoid use of live vaccines.
At patients with an abnormal liver function it is necessary to control carefully the level of the minimum concentration of a sirolimus in blood. Considering the extended drug t1/2 at this category of patients after change of a dose or reception of a shock dose of Rapamun control of concentration of drug in blood it is necessary to see to achievement of its stable level.
Decrease in resistance to infections and predisposition to development of a lymphoma and other malignant diseases, in particular skin, can be a consequence of oppression of immune system.
It is necessary to take precautionary measures, usual for patients with the increased risk of a carcinoma cutaneum: to limit influence of solar and ultraviolet radiation by means of protective clothes and use of creams with high sun-protection effect.
As a result of excessive oppression of immune system increase in a susceptibility to infections, including to the infections caused by conditionally pathogenic microorganisms whose probable effects, sepsis and a lethal outcome, are noted in the section "Side effect" is possible.
As safety and Rapamun's efficiency, as immunodepressive therapy of patients with hepatic and pulmonary transplants, is not established, drug is not recommended to be used at these groups of patients.
In two clinical trials with participation of patients from transplantirovanny de novo a liver use of a sirolimus together with cyclosporine or takrolimusy was followed by increase in frequency of the thrombosis of a hepatic artery in most cases leading to loss of a transplant or death.
It was reported about disturbance or delay of healing of wounds at patients against the background of Rapamun's reception, it is especially frequent at patients whose index of body weight exceeds 30 kg/m ² (to the limfotsela, discrepancy of edges of a wound).
Patients have messages on discrepancy of edges of a bronchial anastomosis with transplantirovanny de novo easy, in most cases with a lethal outcome, at use of a sirolimus as a part of immunodepressive therapy.
At the patients receiving Rapamun liquid delay cases, in particular, peripheral hypostases, stagnation of a lymph, a pleural exudate and an exudative pericardis are described (including hemodynamically significant exudates at children and adults).
At use of a sirolimus allergic reactions, such as anaphylactic/anaphylactoid reactions, exfoliative dermatitis, a Quincke's disease and a vasculitis were noted.
In rare instances combined use of a sirolimus and APF inhibitors led to development of a Quincke's disease.
There are messages on cases of the pneumonia caused by Pneumocystis carinii in the patients who were not receiving antimicrobic prevention. In this regard, within the first 12 months after transplantation it is necessary to carry out the antimicrobic prevention directed against Pneumocystis carinii.
Within 3 months after transplantation prevention of a Cytomegaloviral infection is reasonable.
Rapamun's use for patients after renal transplantation was followed by the increase in level of cholesterol and triglycerides in serum in certain cases demanding medicamentous correction. The patients receiving Rapamun need control for the purpose of identification of a possible lipidemia. If the lipidemia is established, it is necessary to take the appropriate measures including a diet, physical exercises and administration of drugs, reducing cholesterol level. Before purpose of immunodepressants, including Rapamun, and also at the solution of a question of continuation of treatment of patients by Rapamun with a heavy resistant lipidemia it is necessary to estimate a ratio of risk and advantage of this type of therapy.
Good tolerance of Rapamun in combination with inhibitors of HMG-CoA reductase and/or a fibratama is noted. During treatment by Rapamun in a combination with inhibitors of HMG-CoA reductase or a fibratama it is necessary to watch patients in connection with possible development of a rabdomioliz and other side effects described in instructions on a medical use of these medicines.
At joint appointment of Rapamun and cyclosporine it is necessary to carry out monitoring of function of kidneys. It must be kept in mind that patients with the increased creatinine level in serum will require correction of the scheme of treatment by immunodepressants. It is necessary to be careful at co-administration with other medicines which are adversely influencing function of kidneys.
The patients receiving therapy by Rapamun and cyclosporine is more than 3 have some, higher concentration of creatinine in serum and lower level of glomerular filtering, in comparison with the patients of control group receiving cyclosporine and placebo or cyclosporine and Azathioprinum were noted. At patients after successful cancellation of cyclosporine lower level of creatinine in serum and higher level of glomerular filtering in comparison with the patients continuing to receive cyclosporine was noted. Before obtaining additional clinical data joint purpose of cyclosporine and Rapamun as a maintenance therapy is not recommended.
Safety and efficiency of transfer of patients from inhibitors of a kaltsinevrin on Rapamun is not studied.

It is recommended to exercise periodic control of level of excretion of proteins in urine.
Rapamun in the form of tablets, coated, contains sucrose and lactose. Before purpose of drug patients at whom in the anamnesis insufficiency of invertase, lactases and isomaltases, intolerance of fructose, malabsorption of glucose and a galactose, intolerance of a galactose is noted (for example, a galactosemia) should estimate a ratio risk/advantage and, if necessary, to replace Rapamun tablets on Rapamun solution for intake.
INFLUENCE ON ABILITY OF DRIVING AND WORK WITH MECHANISMS
Researches on studying of influence on ability to control of vehicles and use of mechanisms were not conducted.

 

Side effects:

From by-effects most often (at> 10% of patients) met: thrombocytopenia, anemia, hypopotassemia, hypophosphatemia, infections of an urinary path, hypercholesterolemia, hyperglycemia, gipertriglitseridemiya, abdominal pain, to the limfotsela, peripheral hypostases, arthralgia, acne, diarrhea and increase in level of a lactate dehydrogenase.
Frequency of manifestation of any side effect can increase at increase in the minimum concentration of a sirolimus in blood.
In the table given below the by-effects revealed during clinical trials, and also registered after drug entry into the market are specified. The listed by-effects are subdivided according to organ accessory and frequency of manifestation and presented in the table as reduction of gravity of a disease. This list included only those by-effects which, at least, presumably can have causal interrelation with therapy by Rapamun.
Most of patients received the combined immunodepressive therapy which part Rapamun and other immunodepressants was.

System of bodies very frequent (≥10%) frequent (≥1/100 to <1/10) not frequent (≥1/1000 to <1/1000) rare (≥1/10000 to <1/1000)
Infections and invasions of the Infection of urinary tract Sepsis
pneumonia
pyelonephritis
Herpes simplex
the fungal, viral and bacterial infections (caused by mycobacteria, including tuberculosis, Epstein-Barre's virus, a cytomegalovirus and Herpes zoster) 
Tumors are high-quality, malignant and nonspecific (including cysts and polyps) Carcinoma cutaneum Lymphoma
/ post-transplan-tatsionnye limfoprolifera-
tivny disturbances
Hemopoietic and lymphatic system Thrombocytopenia
anemia Trombotichesky thrombocytopenic purpura /
gemolitiko-uraemic syndrome
leukopenia
neutropenia Pancytopenia
Gepatobiliarny frustration Disturbance of hepatic tests 
Immune system   Allergic reactions, including anafilaktoid-nye/
anaphylactic reactions, Quincke's disease, exfoliative dermatitis,
allergic vasculitis
Metabolism Hypercholesterolemia, gipertriglitse-ridemiya (lipidemia) hypopotassemia, hypophosphatemia, hyperglycemia  
Cordial frustration Tachycardia the Exudative pericardis (including hemodynamically significant exudates at children and adults)
Vascular disorders of Limfotsele Deep vein thrombosis Pulmonary embolism Stagnation of a lymph
Respiratory Pneumonitis system, pleural exudate, nasal bleeding Pulmonary bleeding
Gastrointestinal frustration Abdominal pain, diarrhea Stomatitis Pancreatitis
Skin and hypodermic cellulose of the Acne Rash 
Musculoskeletal system Arthralgia Osteonecrosis  
Kidneys and urinary system Proteinuria Nephrotic syndrome
Organism in general peripheral hypostases the slowed-down healing of wounds, hypostases, a pyrexia 
Laboratory tests increase in activity of a lactate dehydrogenase increase in the ALT and nuclear Heating Plant level 

The immunosuppression increases risk of development of a lymphoma and other malignant new growths of skin (see the section "Special Instructions").
Data on Rapamun's hepatotoxic are published. The risk of a hepatotoxic can increase in process of increase in the minimum concentration of a sirolimus in blood. There are messages on exceptional cases of a necrosis of a liver from the death at exceeding of the minimum concentration of a sirolimus in blood.
Cases of intersticial diseases of lungs (including, a pneumonitis and, infrequently, obliterating bronchiolitis with the organized pneumonia and a pneumosclerosis), in certain cases with a lethal outcome were noted at not identified activator, at the patients receiving immunodepressive therapy including Rapamun. In certain cases Rapamun's cancellation or a dose decline led to elimination of intersticial pulmonary process. The risk of a disease can increase in process of increase in the minimum concentration of a sirolimus in blood.
Cases of the slowed-down healing of wounds after transplantation, including discrepancy of fastion, postoperative hernias and a rupture of an anastomosis are described.
At some patients against the background of treatment by Rapamun reversible disturbance of functional activity of sperm was observed.
At patients with the slowed-down function of a transplant reception of a sirolimus can lead to delay of recovery of function of kidneys.
In subgroup of patients with initially reduced glomerular filtration rate (<40 ml/min.) the frequency of the serious undesirable phenomena against the background of reception Rapamuna was higher (including pneumonia, reaction of acute graft rejection, death of a transplant and death).

Interaction with other medicines:

In a wall of intestines and liver сиролимус is exposed to extensive metabolism under the influence of CYP3A4 isoenzyme. Besides, сиролимус is substrate for the R-glycoprotein (P-gp) which is carrying out removal of many medicines localized in a small intestine. Therefore the substances influencing these proteins can influence absorption of a sirolimus and its subsequent removal. CYP3A4 inhibitors (кетоконазол, вориконазол, итраконазол, телитромицин or кларитромицин) reduce metabolism of a sirolimus that leads to increase in its concentration. CYP3A4 isoenzyme inductors (rifampicin or рифабутин) strengthen metabolism of a sirolimus, reducing its concentration. It is not recommended to appoint сиролимус along with powerful inductors or CYP3A4 inhibitors (see the section "Special Instructions").
Cyclosporine (substrate for CYP3A4): Cyclosporine A considerably increases the speed and extent of absorption of a sirolimus. The concomitant use of Rapamun in a dose of 5 mg, then 5 mg in 2 hours and 10 mg in 4 hours after purpose of 300 mg of a microemulsion of cyclosporine A led to increase in AUC of a sirolimus approximately up to 183%, 141% and 80%, respectively. The effect of effect of cyclosporine A was shown also in increase in Smaks and tmaks of a sirolimus. If сиролимус was accepted in 2 hours prior to purpose of a microemulsion of cyclosporine A, no influence on AUC and Smaks of a sirolimus was noted. At the healthy volunteers receiving a single dose of a sirolimus along with cyclosporine (microemulsion) or with the 4th hour interval, the pharmacokinetics of cyclosporine A did not change. Rapamun in 4 hours after reception of a microemulsion of cyclosporine is recommended to appoint.
Rifampicin (inductor CYP3A4): Multiple dose of rifampicin reduced concentration of a sirolimus in blood after a single dose of 10 mg of Rapamun, solution for intake. Rifampicin increased clearance of a sirolimus approximately by 5,5 times and reduced AUC of a sirolimus and Smaks, approximately by 82 and 71%, respectively. It is not recommended to appoint сиролимус along with rifampicin.
Ketokonazol (CYP3A4 inhibitor): Repeated reception of a ketokonazol considerably changed the speed, extent of absorption and influence of a sirolimus: what also 10,9-fold increase, respectively, Smaks, tmaks and AUC testified 4,4-, 1,4-to. It is not recommended to appoint сиролимус along with ketokonazoly.
Vorikonazol (CYP3A4 inhibitor): At joint appointment to healthy volunteers of a sirolimus (2 mg once) and a vorikonazola (inside on 400 mg each 12 hours in the first day, then on 100 mg each 12 hours within 8 days) 7-fold increase in Smaks and 11-fold increase in AUC of a sirolimus was noted on average. It is not recommended to appoint сиролимус along with vorikonazoly.
Diltiazem (CYP3A4 inhibitor): At a concomitant use of 10 mg of Rapamun in the form of solution for intake and 120 mg of diltiazem bioavailability of a sirolimus considerably changed. Смакс, tmaks and AUC of a sirolimus increased, respectively, in 1,4, 1,3 and 1,6 times. Sirolimus did not change pharmacokinetics of diltiazem and its metabolites - a dezatsetildiltiazema and a desmetildiltiazema. At purpose of diltiazem it is necessary to control concentration of a sirolimus in blood and if necessary to adjust a drug dose.
Verapamil (CYP3A4 inhibitor): At purpose of repeated doses of verapamil and a sirolimus in the form of solution for intake the speed and extent of absorption of both connections considerably changed. Смакс, tmaks and AUC of a sirolimus in whole blood increased, respectively, in 2,3, 1,1 and 2,2 times. Values of Smaks, and AUC S-(-) verapamil in plasma increased by 1,5 times, and tmaks was reduced by 24%. It is necessary to control concentration of a sirolimus and, if necessary, to reduce doses of both medicines.
Erythromycin (CYP3A4 inhibitor): At purpose of repeated doses of erythromycin and a sirolimus in the form of solution for intake the speed and extent of absorption of both connections considerably increased. Смакс, tmaks and AUC of a sirolimus in whole blood increased, respectively, in 4,4, 1,4 and 4,2 times. Смакс, tmaks and AUC erythromycin in plasma increased, respectively, in 1,6, 1,3 and 1,7 times. It is necessary to control concentration of a sirolimus and, if necessary, to reduce doses of both drugs.
Oral contraceptives: Clinically significant pharmacokinetic interaction between sirolimusy and 0,3 mg of Norgestrelum / 0,03 in ethinylestradiol mg was not observed. Though results of a research of interaction of a single dose of Rapamun and an oral contraceptive testify to lack of pharmacokinetic interaction, at prolonged treatment by Rapamun it is impossible to exclude possible changes of pharmacokinetics which can affect efficiency of an oral contraceptive.
Other possible interactions: Moderate and weak CYP3A4 inhibitors can reduce metabolism of a sirolimus and increase concentration of a sirolimus in blood (for example, blockers of calcium channels: никардипин; antifungal means: Clotrimazolum, флуконазол; antibiotics: тролеандомицин; and other substances: Bromocriptinum, Cimetidinum, даназол, inhibitors of proteases).
The inductors CYP3A4 can accelerate metabolism of a sirolimus and reduce concentration of a sirolimus in blood (for example, a medicinal plant the St. John's Wort which is made a hole – Hypericum perforatum; anticonvulsants: carbamazepine, phenobarbital, Phenytoinum).
Though in vitro сиролимус inhibits activity of isoenzymes of microsomal system of P450 cytochrome at the person (CYP2C9, CYP2C19, CYP2D6, CYP3A4/5), suppression of activity of these isoenzymes of in vivo is improbable as for this purpose concentration of a sirolimus have to be much higher, than at the patients receiving drug in therapeutic doses. P-gp inhibitors can reduce release of a sirolimus from cells of intestines and promote increase in its concentration in blood.
Grapefruit juice influences CYP3A4 the mediated metabolism and, therefore, it should not be used during Rapamun's reception.
Pharmacokinetic interaction can be observed with gastrointestinal pro-kinetic means, such as цизаприд, Metoclopramidum.
Clinically significant pharmacokinetic interaction of a sirolimus with an acyclovir, atorvastatiny, digoxin, glibenclamide, Methylprednisolonum, nifedipine, Prednisolonum and Trimethoprimum / sulfamethoxazole was not observed.
At simultaneous use of Rapamun with inhibitors of a kaltsinevrin increase in risk of a gemolitiko-uraemic syndrome / a trombotichesky thrombocytopenic purpura / тромботической mikroangiopatiya, induced by inhibitors of a kaltsinevrin is possible.

Contraindications:

Hypersensitivity to a sirolimus or other components of drug. Children's age (experience of use does not suffice, there are only limited data, see the section "Pharmacokinetics").

PREGNANCY AND PERIOD of the LACTATION. Data on Rapamun's use for pregnant women are absent. During pregnancy Rapamun it is necessary to apply only when the estimated advantage for mother exceeds possible risk for a fruit. Effective contraception needs to be begun before treatment by Rapamun and to continue during treatment, and also within 12 weeks after its termination. There are no data on receipt of a sirolimus in breast milk. Considering potential risk for the child, during treatment by Rapamun breastfeeding should be stopped.

Overdose:

Now information on cases of overdose is minimum. At one patient who accepted 150 mg of Rapamun fibrillation of auricles was observed. In general, manifestations of overdose match the by-effects listed in the section "Side effect". In case of overdose it is recommended to carry out a symptomatic treatment. Considering small solubility of Rapamun in water and the high level of linkng with erythrocytes, it is supposed that Rapamun cannot be removed in significant quantities from an organism by means of dialysis.

Storage conditions:

In the place protected from light at a temperature not over 25 to °s.khranit in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Tablets, coated, 1 mg. On 10 tablets in a blister strip packaging (blister) [the laminated film (PVH/PE/Aclar®)/foil aluminum]. On 3 or 10 blisters together with the application instruction in a cardboard pack.