Composition, form of production and packaging
Solution for oral administration from pale yellow to yellow, without visible mechanical inclusions.
1 ml
sirolimus 1 mg
[PRING] polysorbate 80, fosal 50 PG (phosphatidylcholine, propylene glycol, mono- and diglycerides, ethanol, soy fatty acids, ascorbyl palmitate).
60 ml - bottles of dark glass (1) complete with adapter, case, syringes-dispensers plastic (30 pcs.) And protective caps (30 pcs.) - cardboard boxes.
150 ml - bottles of dark glass (1) complete with adapter, case, syringes-dispensers plastic (30 pcs.) And protective caps (30 pcs.) - cardboard boxes.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2011.
PHARMACHOLOGIC EFFECT
Immunosuppressant. Sirolimus inhibits activation of T lymphocytes by blocking calcium-mediated and calcium-independent intracellular signaling. Data from the studies indicate that the mechanism of action of sirolimus differs from the mechanism of action of cyclosporine, tacrolimus and other immunosuppressants. According to experimental data, sirolimus binds to the specific cytosolic protein immunophilin, FK-binding protein-12 (FKPB-12), and the FKPB-12 sirolimus complex inhibits the activation of the enzyme kinase, which is the target for rapamycin in mammals (mTOR - mammalian Target of Rapamycin) and is of fundamental importance for the development of the cell cycle. Inhibition of mTOR results in the blocking of several specific pathways by which the signal is transmitted. Ultimately, the activation of lymphocytes, leading to immunosuppression, is inhibited.
PHARMACOKINETICS
After ingestion, Rapamun (sirolimus) is rapidly absorbed, with C max being achieved approximately 1 hour after a single intake by healthy people, and approximately 2 hours after repeated oral administration by patients in a stable state after allogeneic kidney transplantation. Systemic bioavailability of Rapamun when administered concomitantly with cyclosporine is about 14%. At the subsequent reception the average concentration of sirolimus in blood increases approximately in 3 times.
T 1/2 with repeated oral administration of the drug to patients in a stable state after kidney transplantation was 62 В± 16 hours, and the average C ss was reached after 5-7 days. The ratio reflecting the ratio of blood concentration to plasma concentration is 36. This indicates that sirolimus is largely accumulated in the blood cells.
Sirolimus is a substrate for both the CYP3A4 isoenzyme and the P-glycoprotein. Sirolimus is extensively metabolized by O-demethylation and / or hydroxylation. In the blood there are 7 main metabolites, including hydroxyl, dimethyl, and hydroxydimethyl derivatives. Nevertheless, in human blood sirolimus is the main component of the drug, which determines the immunosuppressive effect of Rapamun by more than 90%. After a single intake of [ 14 РЎ] -sirolimus by healthy volunteers, the bulk (91.1%) of the drug labeled with a radioisotope was detected in the stool, and only a small part (2.2%) was excreted in the urine.
In dialysis children (with a decrease in the glomerular filtration rate by 30-50%) 5-11 years and 12-18 years, it was noted that the average, normalized body weight, the ratio of clearance to filtration (CL / F) is higher in the younger age group group (580 ml / h / kg), compared with the older age group (450 ml / h / kg), whereas in adults the corresponding value is 287 ml / h / kg. Within the limits of each age group the variability of this indicator is noted in wide limits.
In patients with impaired hepatic to moderate-grade liver function (A or B on the Child-Pugh scale), mean values ​​of AUC and T 1/2 of sirolimus were increased by 61% and 43%, respectively, and the mean CL / F was reduced by 33% in comparison with healthy subjects.
In patients with severe hepatic impairment, no assessment of the pharmacokinetics of sirolimus was performed.
In the group of patients with different renal function - from normal to completely absent (hemodialysis patients) - the pharmacokinetic parameters of sirolimus were similar.
INDICATIONS
- Prevention of transplant rejection in adult patients with low or moderate immunological risk after kidney transplantation. It is recommended to appoint Rapamun initially in combination with GCS and a microemulsion of cyclosporine for the first 2-3 months after transplantation. Rapamun therapy can be continued as maintenance therapy with GCS only if cyclosporine is gradually phased out.
DOSING MODE
The drug is prescribed only for oral administration.
Rapamun should be taken continuously either concurrently with a meal or between meals.
Therapy should be carried out under the supervision of a transplant physician.
Initial therapy (within 2-3 months after transplantation): at the usual mode of reception, as soon as possible after transplantation, the dose of 6 mg is administered once, with the subsequent appointment of 2 mg 1 time / day. Subsequently, the Rapamun dose is individually selected in such a way that the minimum concentration of sirolimus in the blood is from 4 ng / ml to 12 ng / ml (chromatographic method). Treatment with Rapamun continues against the background of a simultaneous gradual reduction in the dose of GCS and the microemulsion of cyclosporine.
During the first 2-3 months after transplantation, minimum concentrations of cyclosporine should be maintained between 150 and 400 ng / ml (immune method for determining the concentration).
Supportive therapy: After 4-8 weeks after starting treatment with cyclosporine, the dose should be gradually reduced until complete withdrawal, and the Rapamun dose is selected so that the minimum blood concentrations range from 12 ng / ml to 20 ng / ml (chromatographic method). Rapamun should be taken with GCS.Patients whose cyclosporine withdrawal has failed, or the duration of joint therapy with cyclosporine and Rapamun is not possible for more than 3 months. In clinically justified situations, such patients should abolish Rapamun and prescribe an alternative regimen of immunosuppressant therapy.
Data for the use of sirolimus in patients of the Negroid race is not enough.
In elderly patients (over 65 years of age) experience with Rapamun is not enough to determine if there are differences in response to therapy between patients of this age group and younger ones. In 35 patients older than 65 years after kidney transplantation, the minimum concentrations of sirolimus did not differ from the corresponding concentrations in 822 patients from 18 to 65 years. The results obtained with the appointment of Rapamun tablets to 12 patients over the age of 65 years after kidney transplantation also corresponded to those obtained for adult patients (n = 167) aged 18 to 65 years.
In patients with impaired renal function, dose adjustment is not required.
In patients with severe impairment of liver function, the maintenance dose of Rapamun is recommended to be reduced approximately 2-fold due to the delayed clearance of sirolimus. Shock dose should not be changed.
Monitoring of the therapeutic concentration of sirolimus
In most patients who received Rapamun at a dose of 2 mg 4 hours after cyclosporine, the minimum blood sirolimus concentrations corresponded to a prescribed range of 4 ng / ml to 12 ng / ml (chromatographic method).
To optimize therapy, monitoring of the therapeutic concentration of sirolimus in all patients is required. The concentration of sirolimus in the blood should be monitored particularly carefully in the following groups of patients: (1) patients with impaired hepatic function; (2) during the simultaneous administration of inducers or inhibitors of the cytochrome CYP3A4 system, and also after the end of their administration; (3) in the case of a dramatic dose reduction or cyclosporine discontinuation, since for these patient groups the dose modification is most likely to be required.
To minimize fluctuations in the concentration of sirolimus, Rapamun should be taken at regular intervals with respect to cyclosporine, namely 4 hours after the administration of cyclosporine.
In the optimal case, the choice of Rapamun dose should be based on more than one measurement of the minimum concentration, performed no earlier than 5 days after the last dose change.
Patients can be transferred to tablets after treatment with a solution for oral administration based on an accurate recalculation of the amount of the drug "mg per mg".After transferring the patient to another dosage form or other dosing regimen, it is recommended to measure the minimum concentration of sirolimus within 1-2 weeks
After cyclosporine cancellation, it is recommended to maintain a minimum blood sirolimus concentration of 12-20 ng / ml (chromatographic method). Cyclosporine inhibits the metabolism of sirolimus, so if the dose of Rapamun is not increased, the concentration of sirolimus after the abolition of cyclosporine will decrease. On average, the dose of Rapamun should be 4 times higher, taking into account the absence of pharmacokinetic interaction (2-fold increase) and increased need for immunosuppressive action in the absence of cyclosporine (2-fold increase). The rate of increase in the dose of Rapamun should correspond to the rate of ciclosporin withdrawal.
If it is necessary to adjust the dose with maintenance therapy (after cyclosporine cancellation), it can be done in most patients using the following formula: a new dose of Rapamunum = current dose x (desired concentration / current concentration). The shock dose should be used in addition to the maintenance dose, if it is required to significantly increase the minimum concentration of sirolimus: the Rapamun shock dose = 3 x (the new maintenance dose is the current maintenance dose). The maximum daily dose of Rapamun is 40 mg. If the calculated daily dose exceeds 40 mg because of the impact dose, then the shock dose should be divided into 2 days.Monitoring of the minimum concentration of sirolimus is recommended for at least 3-4 days after the administration of the impact dose.
Recommended concentrations of minimum daily concentrations of sirolimus are determined by chromatographic methods. In clinical practice, both chromatographic and immunoenzymatic methods are used to determine the concentration of sirolimus in whole blood. The results of these methods are not interchangeable. Correction of the dose should be carried out taking into account the method used to determine the minimum concentrations of sirolimus.
When choosing a dose of the drug, Rapamun should focus not only on the results of monitoring therapeutic concentrations, but also take into account clinical symptoms, the results of histological studies and laboratory data.
Cyclosporine and some other medicinal and non-drug substances can influence the action of sirolimus.
Instructions for dilution of oral solution
1. Remove the protective cap from the bottle by pressing the cap from the sides and turning it. The adapter for the syringe should be injected into the vial until it is level with the upper edge of the vial. Do not attempt to remove an already inserted adapter for the syringe from the vial. Insert one of the dispensing syringes into the adapter hole (the syringe plunger is fully lowered).
2. Collect from the vial with a syringe dispenser the prescribed amount of Rapamun solution for oral administration. To do this, carefully pull the syringe dispenser piston until the lower boundary of the black piston line is equal to the corresponding mark on the syringe dispenser. When typing the solution into a syringe, the bottle should be in an upright position. If air bubbles appear in the dispensing syringe, you should return the solution from the syringe to the vial and repeat the procedure again.
3. Accurately measured amount of Rapamun should be transferred with a syringe only in a glass or plastic container containing at least 60 ml of water or orange juice.No other fluids, including grapefruit juice, should be used for breeding. Vigorously mix and immediately drink. Re-pour additional water or orange juice into the vessel, stir vigorously and immediately drink.
4. If it is necessary to take the drug at a certain time of the day, the patient should take the drug with him. Fill the syringe dispenser to the appropriate label and put on the syringe-cap - thus there should be a click. After this, place the syringe dispenser with the cap on it in the case. The syringe with the drug can be stored at room temperature (not exceeding 25 В° C) or in the refrigerator. The drug in the syringe should be used at 24 h.
Syringe dispenser and cap are designed for single use, after which they must be discarded.
SIDE EFFECT
Most often (> 10%): thrombocytopenia, anemia, hypokalemia, hypophosphatemia, urinary tract infections, hypercholesterolemia, hyperglycemia, hypertriglyceridemia, abdominal pain, lymphocele, peripheral edema, arthralgia, acne, diarrhea and LDH elevation.
The frequency of any side effect may increase with an increase in the minimum concentration of sirolimus in the blood. The table below shows side effects identified during clinical trials, as well as those registered after the drug was released to the market. The listed side effects are divided according to the organ and frequency of manifestation and are presented in the table in order of decreasing severity of the disease. This list includes only those side effects that at least presumably may have a causal relationship with the Rapamun therapy.
Most patients received combined immunosuppressive therapy, which included Rapamun and other immunosuppressants.
Very often (? 10%) Often (? 1/100 to <1/10) Sometimes (? 1/1000 to <1/100) Rarely (? 1/10 000 to <1/1000)
Infections and invasions
Urinary tract infections Sepsis, pneumonia, pyelonephritis, herpes simplex, fungal, viral and bacterial infections (caused by mycobacteria, Epstein-Barr virus, cytomegalovirus and Varicella zoster virus)
Tumors benign, malignant and nonspecific (including cysts and polyps )
Skin cancer Lymphoma / post-transplant lymphoproliferative disorders
On the part of the hematopoiesis system
Thrombocytopenia, anemia Thrombotic thrombocytopenic purpura / hemolytic-uremic syndrome, leukopenia, neutropenia Pancytopenia
From the digestive system
Abdominal pain, diarrhea Disturbance of functional liver tests, stomatitis Pancreatitis
Allergic reactions
Anaphylactic / anaphylactoid reactions, angioedema, exfoliative dermatitis, allergic vasculitis
From the side of metabolism
Hypercholesterolemia, hypertriglyceridemia (hyperlipidemia), hypokalemia, hypophosphatemia, hyperglycemia
From the side of the cardiovascular system
Lymphocele Tachycardia, deep vein thrombosis Exudative pericarditis (including hemodynamically significant effusions in children and adults), pulmonary embolism Lymphatic stasis
From the respiratory system
Pneumonitis, pleural effusion, epistaxis Pulmonary haemorrhage
Dermatological reactions
Acne Rash
From the musculoskeletal system
Arthralgia Osteonecrosis
From the urinary system
Proteinuria Nephrotic syndrome
From the body as a whole
Peripheral edema Delayed wound healing, swelling, fever over 38 В° C
From the laboratory indicators
Increase in LDH activity Increase in ALT and ACT activity
Immunodepression increases the risk of developing lymphoma and other malignant neoplasms of the skin.
There are reports of Rapatum's hepatotoxicity, the risk of which may increase as the minimum concentration of sirolimus in the blood rises. There are reports of rare cases of liver necrosis with a fatal outcome when the minimum concentration of sirolimus in the blood is exceeded.
There were cases of interstitial lung diseases (including pneumonitis and sometimes bronchiolitis obliterans with organizing pneumonia and pulmonary fibrosis), in some cases with a fatal outcome in an unidentified pathogen, in patients receiving immunosuppressive therapy, including Rapamun. In some cases, the abolition of Rapamun or a reduction in the dose led to the elimination of the interstitial pulmonary process. The risk of the disease may increase as the minimum concentration of sirolimus in the blood rises.
The cases of delayed healing of wounds after transplantation, including divergence of fascia, postoperative hernia and anastomosis rupture are described.
In patients with delayed graft function, the administration of sirolimus may slow the recovery of kidney function.
CONTRAINDICATIONS
- Children's age (insufficient experience of application, only limited data are available);
- Hypersensitivity to the components of the drug.
PREGNANCY AND LACTATION
Data on the use of Rapamun in pregnant women are absent. In pregnancy, Rapamun should be used only if the intended benefit to the mother exceeds the possible risk to the fetus.
Effective contraception should be started before treatment with Rapamun and continue during the treatment period, and also within 12 weeks after its termination.
It is not known whether sirolimus is excreted in human breast milk. Given the potential risk to the child during treatment Rapamunom breastfeeding should be discontinued.
APPLICATION FOR FUNCTIONS OF THE LIVER
In patients with impaired renal function dose adjustment is required.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
In patients with severe hepatic impairment maintenance dose is recommended to reduce Rapamuna approximately 2 times due to a delayed clearance of sirolimus.Should not change the loading dose.
APPLICATION FOR CHILDREN
Contraindications: children's age (insufficient use of the experience, there are only limited data available).
APPLICATION IN ELDERLY PATIENTS
In elderly patients (over 65 years) experience of Rapamun drug is insufficient to determine whether differences in response to therapy between patients in this age group, there are more young. In 35 patients older than 65 years after the trough concentrations of sirolimus kidney transplantation did not differ from the corresponding concentrations in 822 patients from 18 to 65 years. The results obtained when assigning Rapamuna tablets in 12 patients aged 65 years and after kidney transplantation, also consistent with the results obtained for adult patients (n = 167), aged 18 to 65 years.
SPECIAL INSTRUCTIONS
To date, not received Rapamuna in patients at high immunological risk enough on application data.
There are research experience intended sirolimus together with the following drugs: cyclosporine, azathioprine, mycophenolate mofetil, corticosteroids and cytotoxic antibodies. Rapamuna combination with other immunosuppressive drugs are not well understood.
Application sirolimus, mycophenolate mofetil and corticosteroids in combination with antibodies to the receptors of interleukin-2 is not recommended for the transplant Kidney transplant de novo.
Pharmacokinetics Rapamuna in the body of patients with severe hepatic impairment has not been studied. Patients with impaired hepatic function should be closely monitored level of the minimum blood concentration of sirolimus.
As a result, excessive suppression of the immune system may increase susceptibility to infections, including to infections caused by opportunistic microorganisms are likely consequences of sepsis and death.
Since not established safety and effectiveness as Rapamuna immunosuppressive therapy of patients with liver and lung transplants, the drug is not recommended in these patient groups.
In two clinical studies in patients with liver transplant de novo use of sirolimus together with cyclosporin or tacrolimus accompanied by increased frequency of thrombosis of the hepatic artery, in most cases leads to graft loss or death.
There are reports of bronchial anastomotic dehiscence in patients with de novo patients transplanted lungs, in most cases with a fatal outcome, when used as a part of sirolimus immunosuppressive therapy.
Patients treated Rapamun, fluid retention cases described, in particular, peripheral edema, congestion lymph, pleural effusions, pericardial effusion (including hemodynamically significant effusions in children and adults).
In applying sirolimus marked allergic reactions such as anaphylactic / anaphylactoid reactions, exfoliative dermatitis, angioneurotic edema, and vasculitis.
There have been reports of cases of pneumonia caused by Pneumocystis carinii in patients not receiving antimicrobial prophylaxis. In this regard, during the first 12 months following transplantation should be carried out antimicrobial prophylaxis directed against Pneumocystis carinii.
Within 3 months after transplantation is reasonable prevention of cytomegalovirus infection.
Application Rapamuna in patients after kidney transplantation accompanied by an increase in cholesterol and triglyceride levels in serum, in some cases, to require medical correction. Patients receiving Rapamun, need to be controlled in order to identify possible hyperlipidemia. If hyperlipidemia established, should take appropriate measures, including diet, exercise and taking medications that reduce cholesterol levels. Before the appointment of immunosuppressants, including Rapamun, as well as in deciding whether to continue treatment Rapamunom patients with severe persistent hyperlipidemia need to weigh the risks and benefits of this therapy.
Rapamuna was well tolerated in combination with inhibitors of HMG-CoA reductase inhibitors and / or fibrates. During treatment Rapamunom in combination with inhibitors of HMG-CoA reductase inhibitors or fibrates should be monitored for patients in connection with the possible development of rhabdomyolysis and other side effects as described in the instructions for the medical use of these drugs.
When the joint application Rapamuna cyclosporin and requires monitoring of renal function. It should be borne in mind that patients with elevated serum creatinine levels require correction of immunosuppressive regimens. The caution given concurrently with other drugs that have adverse effects on renal function.
Patients treated with cyclosporine and Rapamunom more than 3 months had higher serum creatinine concentration and lower glomerular filtration rate as compared to the control group patients who received placebo or cyclosporine and cyclosporine and azathioprine. Patients after successfully de cyclosporine had lower serum creatinine and higher rates of glomerular filtration rate as compared to patients who continued to receive cyclosporine. Until further clinical data is not recommended to co-administration of cyclosporine and Rapamuna as maintenance therapy.
Safety and efficacy of moving patients from calcineurin inhibitors to Rapamun not been studied.
It is recommended to periodically monitor protein content in urine.
Immunosuppressants may affect the effectiveness of the vaccine. During treatment with immunosuppressants including Rapamun, vaccination may be less effective.During treatment Rapamunom should avoid the use of live vaccines.
Impact on the ability to drive vehicles and manage mechanisms
Studies on the effects on the ability to drive vehicles and work with the mechanisms have not been conducted.
OVERDOSE
Currently, information on cases of overdose is minimal.
The symptoms mainly coincide with adverse reactions. In one patient, who took Rapamun 150 mg, atrial fibrillation was observed.
Treatment: symptomatic therapy. Given the low solubility of sirolimus in water and a high level of binding to the erythrocytes, it is assumed that the sirolimus can not be removed in significant quantities are excreted via dialysis.
DRUG INTERACTION
In the wall of the intestine and liver sirolimus undergoes extensive metabolism by the action of the isoenzyme CYP3A4. Furthermore, Sirolimus is a substrate for localizing the small intestine of P-glycoprotein, with the assistance of which the elimination of many drugs. Therefore, substances that affect these proteins, can affect the absorption of sirolimus and its subsequent removal. CYP3A4 Inhibitors (ketoconazole, voriconazole, itraconazole, telithromycin or clarithromycin) decrease the metabolism of sirolimus, which leads to an increase in its concentration. Inductors isoenzyme CYP3A4 (rifampicin or rifabutin) increase the metabolism of sirolimus, reducing its concentration. Not recommended for sirolimus together with potent inducers or inhibitors of CYP3A4.
Cyclosporin (substrate CYP3A4) significantly increases the rate and extent of absorption of sirolimus. Simultaneous reception Rapamuna 5 mg, followed by 5 mg at 2 h and 10 mg after 4 hours after administration of cyclosporin A in a dose of 300 mg in the form of microemulsions led to an increase sirolimus AUC up to about 183%, 141% and 80% respectively. The result of action of cyclosporin A and manifested an increase in C max and T max sirolimus blood. In applying sirolimus 2 hours before receiving cyclosporine A microemulsion not observed any influence on AUC and C maxsirolimus in the blood. In healthy volunteers who received a single dose of sirolimus in conjunction with cyclosporin in the form of a microemulsion, or a 4-hour interval, the pharmacokinetics of cyclosporine A was unchanged. It is recommended to assign Rapamun 4 hours after receiving cyclosporine microemulsion.
Repeated rifampicin (inductor CYP3A4) there was a decrease sirolimus concentration in the blood after a single dose Rapamuna 10 mg in the form of solution for oral administration. Rifampicin increased clearance sirolimus approximately 5.5 times and reduced sirolimus AUC and C max of approximately 82% and 71% respectively. Not recommended for sirolimus together with rifampicin.
Repeated reception of ketoconazole (an inhibitor of CYP3A4) significantly changed the speed, the extent of absorption and bioavailability of sirolimus, as evidenced by 4.4-, 1.4-and 10.9-fold increase, respectively, C max , T max and AUC. Not recommended for sirolimus simultaneously with ketoconazole.
When the joint application in healthy volunteers sirolimus in a dose of 2 mg dose and voriconazole (an inhibitor of CYP3A4) inside of 400 mg every 12 hours on the first day, then - 100 mg every 12 hours for 8 days, it was observed on average 7-fold increase in C max and an 11-fold increase in AUC of sirolimus. Not recommended for use in conjunction with sirolimus voriconazole.
In simultaneous reception Rapamuna 10 mg in the form of solution for oral administration of diltiazem and 120 mg bioavailability of sirolimus varied significantly. Cmax , T max and AUC increased sirolimus respectively 1.4, 1.3 and 1.6 times. Sirolimus did not alter the pharmacokinetics of diltiazem and its metabolites dezatsetildiltiazema and desmetildiltiazema. In the appointment of diltiazem is necessary to control the concentration of sirolimus in the blood and adjust the dose if necessary.
When assigning verapamil (an inhibitor of CYP3A4) in multiple doses and sirolimus in solution form for ingestion rate and extent of absorption of both compounds significantly changed. C max , T maxand AUC of sirolimus in whole blood increased respectively by 2.3, 1.1 and 2.2 times. The values of C max and AUC S - (-) in the plasma verapamil increased by 1.5 times, a T max was reduced by 24%. It should control the concentration of sirolimus in the blood and, if necessary, to lower doses of both drugs.
When assigning erythromycin (an inhibitor of CYP3A4) in multiple doses and sirolimus in solution form for ingestion rate and extent of absorption of both compounds significantly increased. C max , T max and AUC sirolimus in whole blood were increased respectively 4.4, 1.4 and 4.2 times. C max , T maxand AUC of erythromycin in plasma were increased respectively by 1.6, 1.3 and 1.7 times. Sirolimus concentration should be monitored and, if necessary, to lower doses of both drugs.
There were no clinically important pharmacokinetic interaction between sirolimus and oral contraceptives containing norgestrel 300 ug / ethinyl estradiol 30 ug. Although the results Rapamuna interaction studies a single dose oral contraceptive and showed no pharmacokinetic interactions with prolonged treatment Rapamunom pharmacokinetics can not exclude possible changes that may affect the effectiveness of oral contraceptive.
Moderate and weak inhibitors of CYP3A4 can slow the metabolism of sirolimus and increase sirolimus concentration in the blood, e.g., calcium channel blockers (nicardipine), antifungals (clotrimazole, fluconazole), antibiotics (troleandomycin) and bromocriptine, cimetidine, danazol, protease inhibitors.
Inducers of CYP3A4 can accelerate the metabolism of sirolimus and decrease sirolimus concentration in the blood (e.g., St John's wort, anticonvulsants - carbamazepine, phenobarbital, phenytoin).
Although in vitro sirolimus inhibit isozymes of microsomal system activity of cytochrome P-450 in humans (CYP2C9, CYP2C19, CYP2D6, CYP3A4 / 5), inhibition of the activity of these isoenzymes in vivo is unlikely, since this sirolimus concentration should be significantly higher than in patients receiving the drug in therapeutic doses. P-glycoprotein inhibitors can reduce the release of sirolimus from intestinal cells and enhance its concentration in the blood.
Grapefruit juice affects CYP3A4-mediated metabolism, and should not be consumed while taking Rapamuna.
Pharmacokinetic interaction can be observed with gastrointestinal prokinetic agents such as cisapride, metoclopramide.
There were no clinically significant pharmacokinetic interaction between sirolimus with acyclovir, atorvastatin, digoxin, glibenclamide, methylprednisolone, nifedipine, prednisolone, and trimethoprim / sulfamethoxazole.
When applied simultaneously with Rapamuna calcineurin inhibitors may increase the risk of hemolytic-uremic syndrome / thrombotic thrombocytopenic purpura / thrombotic microangiopathy inducible calcineurin inhibitors.
In rare cases, the joint use of sirolimus and ACE inhibitors led to the development of angioedema.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be kept out of the reach of children, protected from light at a temperature of from 2 В° to 8 В° C. When stored in original packaging shelf life - 2 years.
After opening the bottle shelf life - 30 days.
When stored in a refrigerator in a vial with a solution of slight haze can occur. If this happens, it is necessary to leave the preparation for a while at room temperature, then shaken gently. The presence of the cloud does not affect the quality of the drug.
