Sertikan (Sertican)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceEverolimusEverolimus
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    • Dosage form: & nbsppills
    Composition:1 tablet contains:
    active substance - everolimus 0.25 mg, 0.5 mg, 0.75 mg or 1 mg; Excipients: butylhydroxytoluene - (corresponding to the dosage of the active substance) 0.025 mg, 0.050 mg, 0.0725 mg, 0.1 mg; lactose monohydrate 2.225 mg, 4.450 mg, b, 675 mg, 8.90 mg; hypromellose - 10.00 mg, 20.00 mg, 30.00 mg, 40.00 mg; magnesium stearate - 0.40 mg, 0.625 mg, 0.938 mg, 1.250 mg; crospovidone - 16.00 mg, 25.00 mg, 37.50 mg, 50.00 mg; lactose anhydrous - 51.10 mg, 74.375 mg, 111.562 mg, 148.75 mg.
    Description:Tablets 0.25 mg: round, flat cylindrical, from white to yellowish, with bevelled edges; marble is allowed; on one side is engraved "C", on the other - "NVR".
    Tablets 0.5 mg: round flat-cylindrical from white to yellowish color tablets with bevelled edges; marble is allowed; on one side is engraved "CH", on the other - "NVR"
    Tablets of 0.75 mg: round flat-cylindrical from white to yellowish color tablets with bevelled edges; marble is allowed; on one side is engraved "CL", on the other side - "NVR".
    Pharmacotherapeutic group:immunosuppressive agent
    ATX: & nbsp

    L.04.A.A.18   Everolimus

    Pharmacodynamics:The active substance of the drug Sertican ® - everolimus - is an inhibitor of the proliferative signal. Everolimus has an immunosuppressive effect by inhibiting the antigen-activated T cell proliferation and, accordingly, the clonal expansion caused by specific T-cell interleukins, for example interleukin-2 and interleukin-15. Everolimus inhibits the intracellular signaling pathway that normally leads to cell proliferation triggered by the binding of these T cell growth factors to the corresponding receptors. The blockade of this signal with everolimus results in stopping cell division in the G1 stage of the cell cycle.
    At the molecular level everolimus forms a complex with the cytoplasmic protein FKBP-12. In the presence of everolimus, inhibition of the phosphorylation of p70 S6 kinase stimulated by the growth factor occurs. Since the phosphorylation of the p70 S6 kinase is under the control of FRAP (the so-called m-TOR), these data suggest that the everolimus-RKBP-12 complex binds to FRAP. FRAP is a key regulatory protein,which controls cellular metabolism, growth and proliferation; the violation of the function of FRAP, thus, explains the arrest of the cell cycle caused by everolimus. Everolimus Thus, it has a different action mechanism than cyclosporin. Pre-clinical models of allotransplantation showed a higher efficacy of the combination of everolimus with cyclosporin than with isolated application of each of them. The effect of everolimus is not limited to the effect on T-cells. It inhibits proliferation of both hematopoietic and nonhematopoietic cells (for example, smooth muscle cells of vessels) stimulated by growth factors.
    Stimulated by growth factor, the proliferation of vascular smooth muscle cells, which is triggered by damage to endothelial cells and leads to the formation of neointima, plays a key role in the pathogenesis of chronic rejection. In experimental studies, inhibition of neointima formation in rats with aortic allotransplant has been shown.
    Pharmacokinetics:Suction
    After oral administration, the maximum concentration (CmOh ) is achieved in 1-2 hours.In patients after transplantation, the concentration of everolimus in the blood is proportional to the dose taken in the dose range from 0.25 mg to 15 mg. Based on the AUC value, the relative bioavailability of the dispersible tablets is 0.90 (90% CI 0.76-1.07) compared to the conventional tablet.
    Effect of food: CmOh and Averolum AUC decreased by 60% and by 16%, respectively, when taking a tablet dosage form with very fatty foods. In order to minimize variability, the Ser- topic® preparation should be taken with or without food.
    Distribution
    The ratio of the concentration of everolimus in the blood and its concentration in the plasma is in the range from 17% to 73% and depends on the concentration in the range from 5 to 5000 ng / ml. In healthy volunteers and patients with impaired liver function of mild and moderate severity, binding to blood plasma proteins is approximately 74%.
    The volume of distribution in the final phase (Vz / F) in patients after kidney transplantation on maintenance therapy is 342 ± 107 liters.
    Metabolism
    Everolimus is a substrate for the isoenzyme CYP3A4 and P-glycoprotein.
    After ingestion in the systemic blood flow are determined everolimus and its six main metabolites, includingthree monohydroxylated metabolites, two hydrolysis products with a broken ring and a phosphodiesterylcholine conjugate of everolimus. These metabolites were also determined when studying toxicity in studies in animals, where their activity was approximately one hundred times lower than the original substance, suggesting that everolimus has pharmacological activity.
    Excretion
    After the administration of a single dose of radio-labeled everolimus to patients after transplantation receiving ciclosporin, most (80%) of radioactivity was detected in the stool, a small amount (5%) was excreted in the urine. The unchanged substance was not determined either in urine or in feces.
    Pharmacokinetics in an equilibrium state
    Pharmacokinetics in patients with kidney and heart transplants receiving everolimus 2 times a day simultaneously with cyclosporine in the form of a microemulsion, was comparable. The equilibrium state was achieved on day 4 with a cumulation in the blood in concentrations that were 2-3 times higher than the concentration in the blood after the application of the first dose. After taking the drug Tmax is 1-2 hours.At doses of 0.75 mg and 1.5 mg twice daily, the mean values FROMmOh are 11.1 ± 4.6 and 20.3 ± 8.0 ng / ml, the average values ​​of AUC are 75 ± 31 and 131 ± 59 ng * h / ml, respectively. At doses of 0.75 mg and 1.5 mg twice daily, C0 everolimus in the blood averaged 4.1 ± 2.1 and 7.1 ± 4.6 ng / ml, respectively (C0 - basal concentration, determined in the morning before taking the next dose). The everolimus exposure remains stable all the time during the first year after transplantation. C0 was highly correlated with the AUC with a correlation coefficient ranging between 0.86 and 0.94. Based on the analysis of pharmacokinetics in patients after transplantation, the total clearance (CL / F) is 8.8 l / h (the spread is 27%), the central volume of distribution (Vc / F) is 110 l (the spread is 36%). The half-life is 28 ± 7 hours.
    Pharmacokinetics in selected patient groups
    Dysfunction of the liver
    Compared with the pharmacokinetics of everolimus in healthy volunteers, when the drug is administered to patients with mild violations of liver function (class A Childe-Pyo), the everolimus AUC increases approximately 1.6-fold, in patients with impaired liver function of moderate severity (grade B
    Child-Pugh) - in 2.1 - 3.3 times, patients with severe violations of the liver (class C Child-Pugh) - 3.6 times.In patients with hepatic insufficiency of mild, moderate and severe severity, the half-life of everolimus was 52, 59 and 78 hours, respectively.
    The increase in the half-life of everolimus promotes a delayed attainment of the equilibrium state.
    In patients with mild hepatic insufficiency (Child-Pugh class A), the dose of the Ser topic should be reduced to approximately 2/3 compared with the usual dose. In patients with moderate-level liver failure (Child-Pugh class B), the everolimus dose should be reduced approximately 2-fold compared with the usual dose. In patients with severe hepatic insufficiency (Child-Pugh class C), the everolimus dose should be reduced to approximately 1/3 of the usual dose.
    Further titration of the dose is carried out based on the data of therapeutic monitoring.
    Renal impairment
    Post-transplantation renal failure (creatinine clearance 11-107 ml / min) did not affect the pharmacokinetic parameters of everolimus.
    Pediatrics
    The clearance of everolimus (CL / F) increased in a linear relationship with the patient's age (from 1 to 16 years), body surface area (0.49-1.92 m2) and body weight (11-77 kg). In the equilibrium state, the clearance was 10.2 ± 3.0 L / h / m2 , the half-life is 30 ± 11 hours.
    Nineteen de novo patients after kidney transplantation from 1 year to 16 years of age received the preparation Sertikan® in the form of tablets dispersible at a dose of 0.8 mg / m2 (maximum -1.5 mg) 2 times daily with cyclosporin in the form of a microemulsion. In these patients, the everolimus AUC was 87 ± 27 ng * h / ml, which was the same for adults receiving 0.75 mg twice daily. In the equilibrium state, the basal concentration (C0) of everolimus was 4.4 ± 1.7 ng / ml.
    Adult patients
    In adult patients aged 16 to 70 years, a decrease in the clearance of everolimus by 0.33% per year was observed.
    No dose adjustment is required.
    Patients of the Negroid race
    Based on the analysis of the pharmacokinetics of everolimus in the population, the overall clearance was higher in patients of the Negroid race, on average by 20%.
    Effect of exposure on efficiency
    In the kidney and heart recipients for 6 months after transplantation, the basal concentration of everolimus (C0) and the frequency of confirmed acute biopsy and thrombocytopenia.
    In liver recipients, the relationship between the concentration of everolimus in the blood and clinical manifestations is less certain, however,a higher concentration of everolimus does not correlate with an increase in the incidence of adverse events.

    Table 1. Effect of exposure on the effectiveness of the drug Sertikan® in patients after transplantation

    Kidney Transplantation

    FROM0 (ng / ml)

    ≤3,4

    3,5-4,5

    4,6-5,7

    5,8-7,7

    7,8-15,0

    Absence of rejection

    68%

    81%

    86%

    81%

    91%

    Thrombocytopenia (<100 x 109/ l)

    10%

    9%

    7%

    14%

    17%

    Heart transplantation

    FROM0 (ng / ml)

    ≤3,5

    3,6-5,3

    5,4-7,3

    7,4-10,2

    10,3-21,8

    Absence of rejection

    65%

    69%

    80%

    85%

    85%

    Thrombocytopenia (<75 x 109/ l)

    5%

    5%

    6%

    8%

    9%

    Liver transplantation

    FROM0 (ng / ml)

    ≤3

    3-8

    ≥8

    Absence of rejection

    88%

    98%

    92%

    Thrombocytopenia

    35%

    13%

    18%

    Neutropenia

    70%

    31%

    44%

    Indications:-Transplantation of the kidney and heart
    Prevention of transplant rejection in adult kidney and heart recipients with low and medium immunological risk receiving basic immunosuppressive therapy with cyclosporin in the form of a microemulsion and glucocorticosteroids.
    -Transplantation of the liver
    Prevention of graft rejection in liver recipients with low and moderate immunological risk receiving basic immunosuppressive therapy with tacrolimus and glucocorticosteroids.
    Contraindications:- Hypersensitivity to everolimus, sirolimus or other components of the drug.
    - Rare hereditary disorders associated with intolerance to galactose,severe lactase deficiency or glucose-galactose malabsorption.
    - Children and teenagers under 18 years.
    Carefully:- The drug should be used with caution in patients with impaired liver function.
    It is recommended to carefully titrate and monitor the concentration of everolimus in the blood plasma in patients with impaired liver function.
    - The use of Certican® with a full dose of cyclosporine in patients after heart and kidney transplantation increases the risk of developing kidney dysfunction.
    To avoid the development of such dysfunction, it is necessary to use a drug with reduced doses of cyclosporine. All patients are recommended regular monitoring of kidney function. With an increase in serum creatinine concentration, consideration should be given to correcting the regimen of immunosuppressive therapy, in particular, to reduce the dose of cyclosporine.
    - Care should be taken when using other drugs that have a negative effect on kidney function.
    Data on the use of the drug Seretikan® without inhibitors of calcineurin (TSC) are limited. Patients who were abolished treatment of TSC showed an increased risk of acute rejection compared to those who continued treatment with these drugs.
    In clinical trials, the preparation Sertikan® was used in combination with a microemulsion of cyclosporine or with tacrolimus, basiliximab and glucocorticosteroids. There are no adequate studies of the combination of the drug Sertican® with other drugs than indicated above.
    - Caution should be exercised when using induction therapy with thymoglobulin (rabbit anti-thymocyte globulin) and an immunosuppression regimen including Sertican® / cyclosporin / glucocorticosteroids. According to clinical studies in cardiac recipients, the simultaneous use of induction therapy with thymoglobulin and the Sertikan® / ciclosporin / glucocorticosteroids (at concentrations recommended for cardiac transplantation) resulted in an increase in the incidence of serious infectious diseases during the first three months after transplantation. These episodes were associated with higher mortality among patients requiring hospitalization and at risk for hyperimmunosuppression.
    - Caution should be exercised while using the Sertican® preparation with CYP3A4 isoenzyme substrates with a narrow therapeutic index(e.g., pimozide, terfenadine, astemizole, cisapride, quinidine or derivatives of ergot alkaloids).
    Simultaneous use of the drug Seretikan® with strong inhibitors or inducers of the isoenzyme CYP3A4 is not recommended (for example, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir and / or rifampicin, rifabutin).
    Pregnancy and lactation:Data on the use of the drug Sertikan® in pregnant women are absent. In experimental studies, the presence of toxic effects on reproductive performance, including embryotoxicity and fetotoxicity, has been shown. It is not known whether there is a potential risk to humans. Do not use the drug in pregnant women, except when the expected benefit of therapy exceeds the potential risk to the fetus. Women of childbearing age should be recommended to use effective methods of contraception during the treatment with the drug Sertikan® and within 8 weeks after the end of therapy.
    It is not known whether everolimus with human breast milk. In experimental studies it was shown that everolimus and / or its metabolites quickly penetrated the milk of lactating rats. Therefore, women who receive Ser- topic® should not breast-feed.
    Dosing and Administration:

    The drug takes inside. Tablets should be taken whole, not crushed before use; to wash down a glass of water.
    Adults
    The recommended initial dose of the drug for patients with kidney and heart transplants is 0.75 mg twice a day; should start using the drug as soon as possible after transplantation. The recommended initial dose of the drug for patients with liver transplant is 1.0 mg 2 times a day, therapy is started approximately 4 weeks after transplantation.
    The daily dose of the drug Sertikan® is always divided into 2 doses; the drug is taken or always along with food, or always without it. Serikan® is administered at the same time as cyclosporin in the form of a microemulsion or tacrolimus. It may be necessary to correct the dosage regimen of the drug Seretikan® taking into account the plasma concentrations achieved, tolerability, individual response to treatment, changes in concomitant drug therapy and the clinical situation.Correction of the dosing regimen can be carried out at intervals of 4-5 days.
    Representatives of the Negroid race
    The incidence of acute rejection of a kidney transplant, confirmed by biopsy, was higher in representatives of the Negroid race than in the rest. According to the limited information available to representatives of the Negroid race, a higher dose of the Sertican® preparation may be required to achieve the same effect as other patients receiving the drug in adult recommended doses.
    Currently available data on efficacy and safety is not sufficient to provide specific recommendations for the application of everolimus in representatives of the Negroid race.
    Patients of advanced age (≥65 years)
    The clinical experience of the use of the drug Sertican® in patients aged ≥65 years is limited. However, there were no clear differences in the pharmacokinetics of everolimus in patients aged ≥65-70 years compared with younger adults.
    Patients with impaired renal function
    In patients with impaired renal function, dose adjustment is not required.
    Patients with hepatic impairment
    Patients with hepatic insufficiency should be carefully monitored basal (C0 ) concentration of everolimus in whole blood. In patients with mild hepatic insufficiency (Child-Pugh class A), the dose of the Ser topic should be reduced to approximately 2/3 compared with the usual dose. In patients with moderate liver failure (Child-Pugh class B), the dose of everolimus should be reduced approximately 2-fold compared with the usual dose. In patients with severe hepatic insufficiency (Child-Pugh class C), the dose of everolimus should be reduced to approximately 1/3 as compared with the usual dose. Further titration of the dose is carried out based on the data of therapeutic monitoring.
    Table 2 presents reduced doses, rounded to the most effective dosage of tablets:

    Table 2. Decrease in the dose of Sertikan® in patients with impaired hepatic function


    Normal liver function

    Hepatic insufficiency of mild degree (Child-Poo A)

    Hepatic insufficiency of medium degree (Child-Poo B)

    Severe hepatic insufficiency (Child-Pyo C)

    Kidney and heart transplantation

    0.75 mg twice daily

    0.5 mg twice daily

    0.5 mg twice daily

    0.25 mg twice daily

    Liver transplantation

    1 mg twice a day

    0.75 mg twice daily

    0.5 mg twice daily

    0.5 mg twice daily

    Therapeutic monitoring

    It is recommended to regularly monitor the therapeutic concentration of everolimus in whole blood. Based on the analysis of exposure-efficacy and exposure-safety, it was found that in patients with C0 ≥ 3.0 ng / ml, the incidence of acute rejection of kidney, heart and liver transplants confirmed by biopsy was lower than in patients with C0 <3.0 ng / ml. The recommended upper limit of the therapeutic concentration range of everolimus is 8 ng / ml. Concentrations above 12 ng / ml have not been studied. Recommended therapeutic levels of everolimus are based on the use of the chromatography method.

    It is especially important to monitor the concentrations of everolimus in the blood in patients with hepatic insufficiency during the simultaneous use of powerful inducers and inhibitors of the isoenzyme CYP3A4, when switching to another dosage form and / or if the dose of cyclosporine is significantly reduced.The concentrations of everolimus in the blood with the use of dispersible tablets may be somewhat lower than with conventional tablets. It is preferable to correct the dosage regimen of the Sertican® preparation based on the values ​​of C0 everolimus, determined more than 4-5 days after the previous dose change. Because the ciclosporin interacts with everolimus, it is possible to decrease the concentration of the latter if the concentration of cyclosporine decreases significantly (C0<50 ng / ml). Recommendations for dosing regimens cyclosporine in combination therapy with the drug Sertikan® in patients after kidney transplantation.
    The drug Sertikan® should not be used for a long time with cyclosporine in a full dose. Reducing the dose of cyclosporine in patients after kidney transplantation, receiving the drug Sertikan®, led to an improvement in kidney function. Reduction of the dose of cyclosporine should be started immediately after transplantation. The recommended values ​​of the residual concentration of cyclosporine in the blood plasma 12 hours after admission    preparation ( FROM0 monitoring) are: in the period up to 1 month - 100-200 ng / ml; 2-3 months - 75-150 ng / ml; 4-5 months -50-100 ng / ml; 6-12 months - 25-50 ng / ml.Before lowering the dose of cyclosporine, it is necessary to make sure that the equilibrium concentration of everolimus in the blood (FROM0) is equal to or higher than 3 ng / ml.
    Recommendations on the dosage regimen of cyclosporine in combination therapy with Sertikan    ® in patients after heart transplantation.
    For patients after heart transplantation in the supporting phase, a dose of cyclosporine should be lowered one month after transplantation in order to improve kidney function. With progression of renal dysfunction, or if the estimated creatinine clearance is <60 ml / min, treatment regimen is necessary.
    Based on the data obtained in clinical studies, it has been established that when everolimus is used in this category of patients, the target plasma cyclosporin concentrations according to the data     FROM0monitoring should be as follows: 200-350 ng / ml to 1 month after transplantation, 150-250 ng / ml after 2 months, 100-200 ng / ml after 3-4 months, 75-150 ng / ml after 5-6 months , 50-100 ng / ml after 7-12 months.
    Before lowering the dose of cyclosporine, it is necessary to make sure that the equilibrium concentration of everolimus in the blood (    FROM0) is equal to or higher than 3 ng / ml.
    Recommendations on the dosing regimen of tacrolimus in combination therapy with the Sertican® preparation in patients after liver transplantation.

    In patients after liver transplantation, the dose of tacrolimus should be reduced in order to minimize the toxic effect of calcineurin inhibitors on the kidneys. The dose reduction for tacrolimus should be started approximately 3 weeks after the onset of combination therapy with the Sertikan® preparation. The dose of tacrolimus should be reduced until the concentration of tacrolimus in the blood is 3-5 ng / ml. With the use of the drug Sertikan® in patients after liver transplantation in combination with a reduced dose of tacrolimus, there was no deterioration in renal function compared to the standard dose of tacrolimus. In clinical studies, no simultaneous use of the Ser- tican® preparation with a full dose of tacrolimus has been performed. Patients who receive the drug Seretikan® concurrently with tacrolimus, regular monitoring of kidney function is recommended.

    In a clinical trial in liver recipients, the abolition of tacrolimus therapy was associated with an increased risk of acute graft rejection.

    Side effects:

    Data on the incidence of adverse reactions were obtained during five clinical trials of the drug Seretikan® in combination with cyclosporine in 2497 kidney recipients and three clinical trials in 1538 heart recipients. In 719 liver recipients in one clinical trial, the drug Serikan® was used in combination with tacrolimus.

    To determine the frequency of undesired reactions, the following criteria were used: very often (≥ 1/10); often (≥1 / 100, <1/10); infrequently (≥1 / 1000, <1/100); rarely (≥1 / 10,000, <1/1000); very rarely (<1/10 000); frequency unknown8.

    The following are undesirable reactions, possibly or probably having a connection with the use of the drug Seretican, which were registered in phase III clinical trials. The type of undesirable reactions detected was approximately the same in patients with kidney, heart and liver transplantation.

    Infectious and parasitic diseases: very often - viral, bacterial and fungal infections, infections of the upper respiratory tract and lower respiratory tract (including pneumonia)1, urinary tract infections2; often - sepsis, wound infection.

    Disturbances from the blood system and lymphatic system:very often - anemia / erythrocytopenia, leukopenia, thrombocytopenia; often - pancytopenia, thrombotic thrombocytopenic purpura / hemolytic uremic syndrome.

    Disorders from the endocrine system: infrequently, hypogonadism in men (decreased testosterone concentration, increased follicle stimulating hormone (FSH) and luteinizing hormone (LH) in the blood plasma).

    Disorders from the metabolism: very often hyperlipidemia (cholesterol, triglycerides), newly diagnosed diabetes, hypokalemia.

    Heart Disease: - effusion to the pericardial cavity3, often, a tachycardia.

    Vascular disorders: very often - increased blood pressure, venous thrombosis; often-lyfocele4, nosebleeds, thrombosis of the vessels of the transplanted kidney; frequency unknown-leukocytoclastic vasculitis. Disturbances from the respiratory system, chest and mediastinal organs: very often - pleural effusion1, coughing1, dyspnea1; infrequently - interstitial lung disease5, the frequency is unknown - pulmonary alveolar proteinosis.

    Disorders from the digestive system: very often - abdominal pain, diarrhea, nausea, vomiting; often pancreatitis, stomatitis / ulceration of the oral mucosa, pain in the oropharynx.

    Disorders from the liver and bile ducts: infrequently - hepatitis of non-infectious etiology, jaundice.

    Disturbances from the skin and subcutaneous tissues: often angioedema edema6, acne, rash, frequency is unknown - erythroderma.

    Disturbances from the musculoskeletal and connective tissue: often - myalgia, arthralgia.

    Disorders from the kidneys and urinary tract: often proteinuria2, necrosis of renal tubules7.

    Violations of the genitals and breast: often - erectile dysfunction.

    Impaired nervous system: very often - a headache.

    Disorders of the psyche: very often, insomnia, anxiety. Benign, malignant and unspecified diseases: often - malignant and unspecified neoplasms, malignant and unspecified skin neoplasias; infrequently: lymphoma / posttransplantation lymphoproliferative syndrome.

    General disorders and disorders at the site of administration: very often - pain, fever, peripheral edema, slowing of reparative processes, often - postoperative hernia.

    Laboratory and instrumental data: often - increased activity of liver enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (ACT), gamma-glutamyltransferase (GGT)).

    References:

    1-occurs frequently in kidney and liver transplantation

    2-occurs frequently in heart and liver transplantation

    3-occurs frequently in heart transplantation

    4-occurs frequently in kidney and heart transplantation

    5-from 0.4 to 2.5% according to clinical studies, depending on the indication and dosage regimen (based on the results of a search in the safety database for the standard MedDRA request for the term "interstitial lung disease")

    6-mainly in patients receiving treatment with ACE inhibitors

    7-occurs frequently with kidney transplantation

    8-based on available data revealed during post-marketing surveillance and when the drug is used in clinical practice, frequency estimation is not possible

    In controlled clinical trials involving 3256 patients receiving the Sertican® preparation in combination with other immunosuppressants and under observation for at least one year, malignancy occurred in 3.1%, 1.0% had skin malignancies, lymphoma or lymphoproliferative diseases 0.60% of patients developed.

    The occurrence of these adverse events may depend on the extent and duration of immunosuppressive therapy. In studies, an increase in serum creatinine concentrations was observed more frequently in patients receiving the Sertican® preparation in combination with a full dose of cyclosporine in the form of a microemulsion than in the control group.

    With the exception of elevated serum creatinine, the safety profile of the drug in studies using the Certican® drug with a reduced dose of cyclosporine was the same as in the 3 main studies where the standard dose of cyclosporine was used, but the overall incidence of adverse events was lower.

    When m-TOR-inhibitors are used, including everolimus, rarely lesions of the lung parenchyma, for example inflammation of the lung parenchyma (pneumonitis) and / or pulmonary fibrosis of non-infectious etiology, in isolated cases with fatal outcome. In most cases, after the withdrawal of therapy with the drug Sertikan® and / or the use of glucocorticosteroids, the disappearance of these undesirable reactions has been noted.

    If any of the side effects listed in the manual are aggravated, or if you notice any other side effects not listed in the instructions, tell your doctor.

    Overdose:In experimental studies it was shown that everolimus has a low acute toxicity potential. After single doses of 2000 mg / kg, no lethal outcome or severe toxicity was observed in mice and rats (control over the range of values). Reports of cases of overdose in humans are very limited. There is only one fact of accidental ingestion of 1.5 mg everolimus by a child at the age of 2 years, with no undesirable effects observed. At a single oral intake in doses up to 25 mg in patients after transplantation, an acceptable tolerance of the drug was noted. In all cases of overdose, general supportive measures should be initiated.
    Interaction:Everolimus is metabolized mainly in the liver and to some extent in the intestinal wall with the participation of the CYP3A4 isoenzyme. Also everolimus is a substrate for the P-glycoprotein carrier protein.
    Consequently, the preparations interacting with the isoenzyme CYP3A4 and / or P-glycoprotein can influence the absorption and subsequent elimination of systemically absorbed everolimus.
    In the event that the patient is taking the Ser- tican® preparation concomitantly with the oral substrates of the CYP3A4 isoenzyme, it is necessary to monitor the undesirable phenomena described in the information on the drug of the corresponding substrate of the CYP3A4 isoenzyme for oral use. All studies of in vivo interaction were conducted without simultaneous application of cyclosporine.
    Simultaneous use with ACE inhibitors increases the risk of developing angioedema.
    Identified undesirable interactions (simultaneous use is not recommended)
    Rifampicin (inductor of isoenzyme CYP3A4)
    In healthy volunteers who received previous therapy with multiple doses of rifampicin, subsequent administration of the drug in a single dose showed an almost 3-fold increase in the clearance of everolimus and a decrease FROMmax by 58% and AUC by 63%. The combined use of the drug Sertican® with rifampicin is not recommended.
    Ketoconazole (inhibitor of the isoenzyme CYP3A4)
    Preliminary treatment of healthy volunteers with multiple doses of ketoconazole followed by a single dose of Ser- topican® resulted in an increase FROMmax everolimus almost 4 times, and AUC - 15 times.
    Expected undesirable interactions (simultaneous use is not recommended)
    Simultaneous use of the drug Seretikan® with potent inhibitors or inducers of the isoenzyme CYP3A4 is not recommended (for example, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, rifabutin).
    Drug interactions, which should be taken into account when using simultaneously
    Drugs affecting the activity of the drug Sertican®
    Cyclosporin (an inhibitor of the isoenzyme CYP3A4 / P-glycoprotein)
    Bioavailability of everolimus significantly increased with simultaneous application of cyclosporine. In a single dose study in healthy volunteers ciclosporin in the form of a microemulsion (Sandimmun Neoral) increased the everolimus AUC by 168% (from 46% to 365%) and FROMmax - by 82% (from 25% to 158%) compared with the use of only one everolimus. When changing the dose of cyclosporine, a correction of the dosage regimen of everolimus may be required.
    Erythromycin (inhibitor of the isoenzyme CYP3A4)
    Preliminary treatment of healthy volunteers with multiple doses of erythromycin followed by a single dose of the drug Seretican resulted in an increase in Cmax everolimus by a factor of 2, and AUC by 4.5-fold.
    Verapamil (inhibitor of the isoenzyme CYP3A4)
    In the preliminary treatment of healthy volunteers with multiple doses of verapamil followed by a single dose of the drug Sertican®, FROMmax everolimus increased 2.3-fold, and AUC-3.5-fold.
    Effect of the drug Sertikan® on the activity of concomitantly used drugs
    The clinical significance of the effect of the drug Seretikan® on the pharmacokinetics of cyclosporine is minimal in patients with a kidney and heart transplant receiving ciclosporin in the form of a microemulsion.
    Octreotide
    With simultaneous application of everolimus and octreotide Cmin The latter increased with the average geometric ratio (everolimus to placebo) in 1,47 times.
    Atorvastatin (substrate of the isoenzyme CYP3A4) and pravastatin (P-glycoprotein substrate)
    The administration of a single dose of the drug with atorvastatin or pravastatin by healthy volunteers did not clinically significantly affect the pharmacokinetics of atorvastatin, pravastatin and everolimus, as well as the overall bioreactivity of HMG-CoA reductase in plasma.However, these results can not be extrapolated to other HMG-CoA reductase inhibitors.
    Patients receiving HMG-CoA reductase inhibitors should be monitored for rhabdomyolysis and other adverse events in accordance with the instructions for the use of the above agents.
    Midazolam (substrate of the isoenzyme CYP3A4A)
    In studies everolimus shows a weak inhibitory activity against the isoenzyme CYP3A4A. In healthy volunteers who received previous therapy with multiple doses of everolimus, subsequent administration of midazolam in a single dose showed an increase FROMmOh midazolam in 1,25 times and increase in AiS (terminal) midazolam in 1,3 times. The half-life of midazolam did not change.
    Expected drug interactions, which should be considered when using simultaneously
    Drugs affecting the activity of the drug Sertican®
    Moderate inducers of the isoenzyme CYP3A4 can increase the metabolism of everolimus and decrease the concentrations of everolimus in the blood (for example, St. John's Wort, an anticonvulsant: carbamazepine, phenobarbital, phenytoin; antiviral drugs, including for the treatment of HIV infection: efavirenz, nevirapine).
    Moderate inhibitors of the isoenzyme CYP3A4 and P-glycoprotein can increase the concentration of everolimus in the blood (eg, antifungal agents - fluconazole; blockers of "slow" calcium channels nicardipine, diltiazem; antiviral drugs, including for the treatment of HIV infection: nelfinavir, indinavir, amprenavir).
    P-glycoprotein inhibitors can reduce the release of everolimus from intestinal cells and increase the concentration of everolimus in the serum.
    In vitro everolimus was a competitive inhibitor of CYP3A4 and CYP2D6 isoenzymes, potentially increasing plasma concentrations of drugs released with the participation of these enzymes. Therefore, caution should be exercised when using the Sertican® preparation with the substrates of CYP3A4 and CYP2D6 isoenzymes with a narrow therapeutic index (for example, pimozide, terfenadine, astemizole, cisapride, quinidine or derivatives of ergot alkaloids).
    Tacrolimus (inhibitor of the isoenzyme CYP3A4)
    Tacrolimus inhibits only CYP3A4 without affecting the activity of P-glycoprotein, and thus has no clinically significant effect on the pharmacokinetics of everolimus.
    Another possible interaction
    Grapefruit and grapefruit juice influence the activity of cytochrome P450 and P-glycoprotein, so their use should be avoided during treatment Sertikan® preparation.
    Vaccination
    Immunosuppressants may influence the response during vaccination; against the background of drug treatment, vaccination may be less effective. Use of live vaccines should be avoided.
    Special instructions:Use in children
    Data on the use of the drug Sertikan® in children and adolescents is not enough to recommend the use of the drug in this category of patients. However, there are limited studies on the use of the drug Seretikan ® in pediatrics for kidney transplantation.
    Treatment with Sertikan® should be initiated and conducted only by physicians with experience of immunosuppressive therapy after organ transplantation. It is necessary to regularly determine the concentration of everolimus in whole blood. The use of the drug Sertican® in patients with high immunological risk has not been adequately studied.
    It is not recommended simultaneous use of the drug with potent inhibitors of the isoenzyme CYP3A4 (for example, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir) and inductors (for example, rifampicin, rifabutin), except in cases when the expected benefit of such therapy exceeds the potential risk. It is recommended to monitor the concentrations of everolimus in whole blood with simultaneous use with inducers or inhibitors of the CYP3A4 isoenzyme and after their cancellation.
    In patients receiving therapy with immunosuppressive drugs, including the drug Sertican®, the risk of developing lymphomas and other malignant diseases, especially of the skin, is increased. Absolute risk is associated with the duration and intensity of immunosuppression, than with the use of a particular drug. It is necessary to regularly monitor the condition of patients to detect skin lesions. Patients should be advised to minimize exposure to ultraviolet radiation, sunlight and the use of appropriate sunscreen.
    The use of the drug Sertican® was associated with the development of angioedema. In the vast majority of such cases, patients simultaneously received ACE inhibitors as concomitant therapy.
    With the use of the drug Seretikan® simultaneously with TSC in patients after transplantation, the development of proteinuria is possible. The risk of developing proteinuria is proportional to the concentration of everolimus in the blood serum. In kidney recipients who already have mild proteinuria and receive supportive TSC-based immunosuppression, there has been an increase in proteinuria when the TSC is completely replaced with the Certikan® preparation. This deterioration was reversible, provided that Sericcan® therapy was discontinued and returned to TSC-based therapy. The safety and effectiveness of the transition from TSC to Sertikan® in this patient population has not been established. Patients receiving Sertican® should be monitored for proteinuria.
    Simultaneous use of the drug Seretikan® and preparations of TSC can increase the risk of the emergence of TSC-induced hemolytic uremic syndrome, thrombocytopenic purpura, thrombotic microangiopathy.
    Against the background of the use of the drug during the first 30 days after transplantation, there was an increased risk of developing a thrombosis of the renal artery or vein, leading to rejection of the graft.
    The drug Sertikan®, like other m-TOR inhibitors, can worsen the process of wound healing, lead to post-transplant complications requiring surgical intervention: divergence of wound edges, accumulation of exudate, infection of the wound. To the development of lymphocele, recipients of the kidney with excessive body weight tend. Patients after heart transplantation may develop pericardial and pleural effusions. In patients after liver transplantation, the frequency of postoperative hernia development was increased.
    Against the background of the use of the drug Seretikan®, the risk of the newly diagnosed diabetes mellitus is increased, therefore careful monitoring of the glucose concentration in the blood serum is necessary. There are reports of reversible azoospermia and oligospermia in patients receiving m-TOR inhibitors. Preclinical toxicological studies have shown that everolimus can reduce spermatogenesis. The risk of developing male infertility may be a potential undesirable phenomenon of prolonged therapy with the drug Sertican®.
    Patients receiving immunosuppressive drugs, including Ser- tican®,are at risk of developing infections, especially those caused by opportunistic pathogens (bacteria, fungi, viruses, protozoa). There are reports of the development of fatal infections and sepsis in the use of the drug. Of the opportunistic infections that occur in patients receiving immunosuppressive therapy, it is possible to develop VC of virus-associated nephropathy leading to rejection of the kidney transplant and potentially fatal JC virus-associated progressive multiple leukoencephalopathy (PML). These infections are caused by the general complex of immunosuppression and should be considered for differential diagnosis in case of a decrease in the function of the transplanted kidney and in the development of neurologic symptoms. In clinical trials of the drug, the development of pneumonia caused by Pneumocystis jiroveci (carini) and cytomegalovirus infection after transplantation was carried out, especially in patients at increased risk of developing this infection.
    There are data on the development of interstitial lung disease (intraparenchymatous inflammation (pneumonitis), as well as fibrosis of non-infectious etiology,accompanied in some cases by a lethal outcome) among patients receiving drugs with rapamycin and its derivatives, including the drug Sertikan®.
    In patients with a persistent clinical picture of pneumonia with ineffective antibiotic therapy and the exclusion of infectious, neoplastic and other non-drug-related processes, interstitial lung involvement should be suspected. As a rule, the condition is resolved independently after discontinuation of the Ser topic: and / or addition to the therapy of glucocorticosteroids.
    Simultaneous use of the drug Seretikan® with cyclosporin in the form of a microemulsion or tacrolimus in patients after transplantation may be associated with an increase in serum cholesterol and triglycerides, which may require appropriate treatment. Patients receiving Sertican® should be monitored for hyperlipidemia; if necessary, be treated with lipid-lowering agents and prescribe the appropriate corrective diet.It is necessary to assess the risk / benefit ratio for patients who have hyperlipidemia before initiating therapy with immunosuppressive drugs, including Ser- topican®. Also, the risk / benefit ratio of the continuation of Ser- tican® therapy in patients with severe reflux hyperlipidemia should be assessed.
    Patients receiving HMG-CoA reductase inhibitors and / or fibrates should be monitored for rhabdomyolysis and other adverse events caused by the above medicines.
    Effect on the ability to drive transp. cf. and fur:Studies of the effect of the drug Sertican® on the ability to drive vehicles and work with mechanisms have not been carried out.
    Form release / dosage:Tablets 0.25 mg.
    Tablets 0.5 mg.
    Tablets 0.75 mg.
    Tablets 1.0 mg.

    Packaging:Tablets 0.25 mg: 10 tablets in a blister PA / Alum / PVC. For 5, 6, 10 and 25 blisters together with instructions for use in a cardboard bundle.
    Tablets 0.5 mg: 10 tablets in a blister PA / Alum / PVC. For 5, 6, 10 and 25 blisters together with instructions for use in a cardboard bundle.
    Tablets of 0.75 mg: 10 tablets in blister PA / Alum / PVC. For 5, 6, 10 and 25 blisters together with instructions for use in a cardboard bundle.
    Tablets 1.0 mg: 10 tablets in a blister PA / Alum / PVC. For 5, 6, 10 and 25 blisters together with instructions for use in a cardboard bundle.

    Storage conditions:In dry, dark place at a temperature of no higher than 25 ° C.
    The drug should be stored out of the reach of children.
    Shelf life:3 years.
    Do not use the drug after the expiry date printed on the package.
    Terms of leave from pharmacies:On prescription
    Registration number:LS-002282
    Date of registration:29.07.2011
    The owner of the registration certificate:Novartis Pharma AGNovartis Pharma AG Switzerland
    Manufacturer: & nbsp
    Representation: & nbspNOVARTIS PHARMA LLCNOVARTIS PHARMA LLC
    Information update date: & nbsp2016-01-22
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