Composition, form of production and packaging
The tablets covered with a cover of white color, the triangular form, with marking of red color "RAPAMUNE 1 mg".
sirolimus 1 mg
1 tablet, coated with a shell, contains: sirolimus nanosensitive dispersed 150 mg / 1 g (sirolimus 100% (active substance) - 1.02 mg, poloxamer 188 - 0.51 mg).
[PRING] lactose monohydrate, macrogol 8000, magnesium stearate, talc, macrogol 20000, glyceryl monooleate (60%), pharmaceutical glaze (shellac solution # 4), calcium sulfate, microcrystalline cellulose, sucrose, titanium dioxide, povidone K29-32,? -tocopherol acetate, carnauba wax, red ink - opaque S-1-15095 (shellac solution about 45% (contains 20% esters) in ethanol, iron dye oxide red (E172), isopropanol, butanol, propylene glycol, ammonia water, simethicone ).
10 pieces. - blisters (3) - packs of cardboard.
10 pieces. - blisters (10) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2011.
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.
The maintenance regimen of sirolimus, without cyclosporine, has been studied in patients with a low and moderate immunological risk of graft loss. The study involved patients with an allogeneic kidney transplant of the deceased or kidney of a living donor. In addition, recipients with transplanted grafts in which previous grafts survived for at least 6 months after transplantation were included in the study. Cyclosporine was not abolished in patients who underwent acute rejection of a grade 3 Banff transplant or who were on dialysis, or with a serum creatinine content of> 400 Ојmol / L, or with renal insufficiency that did not allow the elimination of cyclosporine. The effect of the drug in patients with high immunological risk of graft loss has not been sufficiently studied in this study, which does not allow us to recommend the treatment regimen for this group of patients.
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 вЂ‹вЂ‹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 (class C on the Child-Pugh scale), mean values вЂ‹вЂ‹of AUC and T 1/2 of sirolimus were increased by 210% and 170%, respectively, and the mean CL / F was reduced by 67% healthy subjects. A longer T 1/2 of sirolimus as a result of impaired liver function led to a slower achievement of its equilibrium state in the body.
In the group of patients with different kidney function - from normal to completely absent (hemodialysis patients) - the pharmacokinetic parameters of sirolimus were similar.
In healthy volunteers, after taking the drug in a single dose in the form of tablets, the average bioavailability of sirolimus is approximately 27% higher than the corresponding value after taking the solution; the mean C max is 35% lower, and the mean T max in blood plasma is 82% higher. After achieving the equilibrium state of sirolimus in recipients of renal transplants, the difference in bioavailability was less pronounced. In a randomized study involving 477 patients, the therapeutic equivalence of the two dosage forms was demonstrated. When transferring patients from oral solution to tablets, it is recommended to prescribe the previous dose and monitor the minimum concentration of sirolimus in the blood after 1-2 weeks to ensure that it remains within the recommended range.
24 healthy volunteers treated with Rapamun tablets along with high-fat food showed an increase of Cmax , Tmax and AUC by 65%, 32% and 23%, respectively. To minimize fluctuations, Rapamun tablets should be taken always with or without food. Do not consume grapefruit juice, which affects CYP3A4-mediated sirolimus metabolism.
Initial therapy (2-3 months after transplantation): in most patients who receive Rapamun tablets with a dose of saturation (6 mg) and then switch to a maintenance dose of 2 mg 1 time / day, C min sirolimus in the blood quickly reach C ss , corresponding to a given interval (from 4 to 12 ng / ml according to the chromatographic analysis).
According to monitoring of all patients receiving cyclosporine as a concomitant therapy, the average concentration of sirolimus in the blood (chromatographic method) was 8.6 В± 3 ng / ml with a daily dose of 2.1 В± 0.7 mg.
Supportive therapy: 3-12 months after ciclosporin withdrawal, the minimum concentration of sirolimus in the blood (chromatographic method) was 19 В± 4.1 ng / ml against the background of taking daily doses of 8.2 В± 4.2 mg. Thus, the dose of sirolimus was approximately 4 times higher than the calculated dose.
- 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.
The drug is prescribed only for oral administration.
Rapamun should be taken continuously either concurrently with a meal or between meals. It is not recommended to break the integrity of the tablets before swallowing them because the bioavailability of the drug after crushing, chewing or breaking the tablets has not been studied.
Therapy should be carried out under the supervision of a transplant physician.
Initial therapy (within 2-3 months after transplantation): in the usual mode of reception, as soon as possible after transplantation, the dose of 6 mg is administered once, with the subsequent administration 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 the drug is completely discontinued and the Rapamun dose is selected so that the minimum blood concentrations are 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 combined therapy with cyclosporine and Rapamun is not longer 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 2 mg at 4 hours after cyclosporine, the minimum concentrations of sirolimus in the blood corresponded to a predetermined interval from 4 ng / ml to 12 ng / ml (according to chromatographic analysis).
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 ciclosporin discontinuation, as these groups of patients are most likely to require dose modification.
To minimize fluctuations in the concentration of sirolimus, Rapamun should be taken at constant 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.
After the beginning of treatment with Rapamun's solution, the patient can continue therapy with Rapamun in tablets while maintaining the exact dose. 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 ciclosporin withdrawal it is recommended to maintain a minimum concentration of sirolimus in the blood at a level 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 performed 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.
After a dose change or a Rapapur dose is taken in patients with severe hepatic insufficiency due to a slower achievement of the equilibrium state, the control of the sirolimus concentration in the blood should be performed every 5-7 days until 3 consecutive determinations of the sirolimus concentration confirm the achievement of C ss .
The calculation of the 24-hour minimum concentration of sirolimus is based on the results of chromatographic methods. Various approaches have been used to measure the sirolimus concentration in the blood. Currently, the concentrations of sirolimus in the blood are measured by both chromatographic and immunoenzymatic methods. The concentration values вЂ‹вЂ‹obtained by these methods are not interchangeable. Using immunoassay systems, one should always follow the manufacturer's recommendations in order to correlate the obtained values вЂ‹вЂ‹with those obtained by standard chromatographic methods. All concentrations of sirolimus given in this document were measured by chromatographic methods or converted to the corresponding equivalent values. To determine the desired minimum concentration of sirolimus, correction should be made in accordance with the methods used.
When choosing a dose of the drug, Rapamun should focus not only on the results of monitoring therapeutic concentrations, but also pay special attention to clinical symptoms, the results of histological examination and laboratory data.
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
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, pericardial effusion (including haemodynamically significant effusions in children and adults), pulmonary embolism, lymph stagnation
From the respiratory system
Pneumonitis, pleural effusion, epistaxis Pulmonary hemorrhage
From the musculoskeletal system
From the urinary system
Proteinuria Nephrotic syndrome is
part of the body as a whole
peripheral edema Delayed wound healing, edema, pyrexia
From laboratory indicators
Increased activity of LDH and ALT increased activity ACT
Immunosuppression increased risk of lymphomas and other malignant tumors of the skin.
There are reports of hepatotoxicity Rapamuna risk which may increase as the increase of the minimum concentration of sirolimus in the blood. There have been reports of rare cases of hepatic necrosis with fatal outcome in excess of the minimum concentration of sirolimus in the blood.
Cases of interstitial lung disease (including pneumonitis and sometimes bronchiolitis obliterans with organizing pneumonia and lung fibrosis), in some cases fatal unidentified at the exciter, in patients receiving immunosuppressive therapy, including Rapamun. In some cases Rapamuna abolition or reduction in dose resulted in a pulmonary interstitial elimination process. The risk may increase as the increase of the minimum concentration of sirolimus in the blood.
There are cases of delayed healing after transplantation, including the divergence fascias, postoperative herniation and rupture anastomoses.
In some patients during treatment with Rapamunom observed reversible infringement of functional activity of sperm.
In patients with delayed graft function receiving sirolimus could slow down the recovery of renal function.
In the subgroup of patients with initially reduced glomerular filtration rate (<40 ml / min), the frequency of serious adverse events in patients receiving Rapamuna was higher (including pneumonia, acute graft rejection reaction, graft destruction and death).
- Children's age (insufficient use of the experience, there are only limited data);
- Hypersensitivity to the components of the drug.
PREGNANCY AND LACTATION
Data on the use Rapamuna in pregnant women are missing. Rapamun during pregnancy should only be used in cases where the expected benefit to the mother outweighs the potential risk to the fetus.
Effective contraception should be started prior to treatment Rapamunom and continue during treatment and for 12 weeks after it.
It is not known whether sirolimus is excreted in breast milk in humans. 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
Contraindicated: children's age (insufficient use of the experience, there are only limited data);
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.
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.
Patients with impaired hepatic function should be closely monitored level of the minimum blood concentration of sirolimus. Given the extended T 1/2drug in this category of patients after changing the dose or bolus Rapamuna reception control drug concentration in the blood should be carried out to achieve a stable level of its
reduced resistance to infection and predisposition to lymphomas and other malignant diseases, particularly of the skin may be due to suppression of the immune system. It is necessary to take precautions usual for patients with increased risk of skin cancer: limit exposure to sun and ultraviolet radiation using protective clothing and use creams with high sun protection effect.
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.
Reported abuse or slowing of wound healing in patients in patients receiving Rapamuna particularly frequently in patients body mass index greater than 30 kg / m 2(lymphocele, dehiscence).
There are reports of bronchial anastomotic dehiscence in patients with lung transplant de novo, 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 coadministered 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. Care must be taken with concomitant administration with other drugs that adversely affect kidney 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 carry out periodic monitoring of the level of protein excretion in the 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.
Rapamun in the form of tablets, coated tablets, comprises sucrose or lactose. Before assigning the drug to patients who have a history of failure sucrase, lactase and isomaltase, fructose intolerance, malabsorption of glucose and galactose, galactose intolerance (e.g., galactosemia) should assess risk / benefit ratio, and if necessary, replace Rapamun pill Rapamun solution for oral administration.
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.
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.
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 1 day, followed by 100 mg every 12 hours for 8 days, it was observed on average 7-fold increase in C max and 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.