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Instruction for use: Sertican

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Dosage form: Tablets; dispersible tablets

Active substance: Everolimusum

ATX

L04AA18 Everolimus

Pharmacological group:

Immunodepressants

The nosological classification (ICD-10)

T86.1 Kidney transplant death and rejection: Reaction of acute rejection of a transplanted kidney; Refractory tissue rejection in patients after allogeneic kidney transplantation

T86.2 Dying and rejection of a heart transplant

Z94.0 Presence of transplanted kidney: Allogeneic kidney transplantation; Allogeneic kidney transplant; Kidney allograft; Allotransplantation of the kidney; Kidney Transplantation

Z94.1 Presence of a transplanted heart: Heart transplant

Composition

Tablets are dispersible - 1 tab.

active substance: Everolimus 0.1 mg; 0.25 mg

Auxiliary substances: butylhydroxytoluene; Lactose monohydrate; Hypromellose, magnesium stearate; Silicon dioxide colloidal anhydrous; Crospovidone; Anhydrous lactose

Tablets - 1 table.

active substance: Everolimus 0.25 mg; 0.5 mg; 0.75 mg; 1 mg

Auxiliary substances: butylhydroxytoluene (according to the dosage of the active substance) - 0.025 / 0.05 / 0.0725 / 0.1 mg; Lactose monohydrate 2.225 / 4.45 / 6.675 / 8.9 mg; Hypromellose - 10/20/30/40 mg; Magnesium stearate - 0.4 / 0.625 / 0.938 / 1.25 mg; Crospovidone - 16/25 / 37.5 / 50 mg; Lactose anhydrous - 51.1 / 74.375 / 111.562 / 148.75 mg

Description of dosage form

Tablets of 0.25 mg: round, flat, white to yellowish, with beveled edges, marble allowed, on one side marking "C", on the other - "NVR".

Tablets of 0,5 mg: round, flat, from white to yellowish color, with bevelled edges, marble is allowed, on one side marking "CH", on the other - "NVR".

Tablets of 0.75 mg: round, flat, from white to yellowish color, with bevelled edges, marble is allowed, on one side marking "CL", on the other - "NVR".

Tablets 1 mg: round, flat, from white to yellowish color, with bevelled edges, marble is allowed, on one side there is a marking "CU", on the other side - "NVR".

Tablets dispersible 0,1 mg: round, flat, from white to yellowish color, with bevelled edges, marble is allowed, on one side marks "I", on the other - "NVR".

Tablets dispersible 0,25 mg: round, flat, from white to yellowish color, with bevelled edges, marble allowed, on one side marking "JO", on the other - "NVR".

Pharmachologic effect

Mode of action - Immunosuppressive.

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 proliferation of T cells and, accordingly, the clonal expansion caused by specific IL-T cells (eg, IL-2 and IL-15). Everolimus inhibits the intracellular signaling pathway, which 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-FKBP-12 complex binds to FRAP. FRAP is a key regulatory protein that controls cellular metabolism, growth and proliferation; The violation of the function of FRAP, thus, explains the cessation of the cell cycle caused by everolimus. Everolimus has, therefore, an action mechanism different from the cyclosporin. In preclinical models of allotransplantation, a higher efficacy of the combination of everolimus with cyclosporine was shown, compared with the isolated use of each.

The effect of everolimus is not limited to the effect on T cells. It inhibits the proliferation of both hematopoietic and nonhematopoietic cells (eg, smooth muscle cells) stimulated by growth factors. Stimulated by growth factor, the proliferation of smooth muscle cells of the vessels, 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 was shown.

Pharmacokinetics

Suction. After oral administration Cmax is achieved after 1-2 hours. In patients after transplantation, the concentration of everolimus in the blood is proportional to the dose in the dose range from 0.25 to 15 mg. Based on the AUC indicator, the relative bioavailability of the dispersible tablets is 90% as compared to the tablets.

Influence of food: Cmax and AUC of everolimus decreased by 60 and 16%, respectively, when taking tablets with very fatty foods. To minimize variability, the Sertopic® preparation should be taken either concomitantly 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 moderate impairment of liver function, plasma protein binding is approximately 74%. VSS in the final phase in patients after kidney transplantation on maintenance therapy is (342 ± 107) l.

Metabolism. Everolimus is a substrate of CYP3A4 and P-glycoprotein. The main ways of metabolism, found in humans, were monohydroxylation and O-dealkylation. The two main metabolites are formed by the hydrolysis of cyclic lactone. None of them has a significant immunosuppressive activity. In the systemic blood flow there is mainly everolimus.

Excretion. After administration of a single dose of radiolabeled everolimus to patients after transplantation receiving cyclosporin, most of the (80%) 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 renal and cardiac graft who received everolimus twice daily with cyclosporine in the form of a microemulsion was comparable. The equilibrium state was achieved on the 4th day with 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. When taking the drug at doses of 0.75 and 1.5 mg twice a day, the mean Cmax values are (11.1 ± 4.6) ng / ml and (20.3 ± 8 , 0) ng / ml, the average values of AUC were (75 ± 31) ng × h / ml and (131 ± 59) ng × h / ml, respectively. When taking the drug at doses of 0.75 and 1.5 mg twice a day, C0 everolimus in the blood is, on average, (4.1 ± 2.1) ng / m or (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 is 8.8 l / h (range - 27%), the central apparent VSS is 110 l (range - 36%). T1 / 2 is (28 ± 7) h.

Pharmacokinetics in special clinical cases

Dysfunction of the liver. In 8 patients with moderate hepatic impairment (class B on the Child-Pough scale), the everolimus AUC increased approximately 2-fold compared to that in 8 healthy volunteers. The AUC index positively correlated with serum bilirubin concentration and PV increase and was negatively correlated with serum albumin concentration. If the concentration of bilirubin was> 34 μmol / L, PV was> 1.3 INR (prolongation> 4 sec) and / or albumin concentration was <35 g / l, there was a tendency for AUC to increase in patients with moderate hepatic impairment. The effect of severe hepatic insufficiency (class C Child-Pugh) on AUC has not been studied, but it is probably the same or more pronounced than the impact of moderate hepatic insufficiency.

Impaired renal function. Post-transplantation renal failure (Cl creatinine - 11-107 ml / min) did not affect the pharmacokinetic parameters of everolimus.

Pediatrics. Cl of everolimus increased in linear dependence on 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, Cl was (10.2 ± 3.0) l / h / m2, T1 / 2 - (30 ± 11) h.

Nineteen de novo patients after kidney transplantation from 1 year to 16 years of age received the drug Sertican® in the form of tablets dispersible at a dose of 0.8 mg / m2 (maximum - 1.5 mg) 2 times a day with cyclosporine in the form of a microemulsion. In these patients, the everolimus AUC was (87 ± 27) ng × h / ml, and was consistent with that in adults receiving 0.75 mg 2 times / day. In the equilibrium state, the basal concentration was (4.4 ± 1.7) ng / ml.

Adult patients. In adult patients aged 16 to 70 years, there was a decrease in clearance of everolimus at 0.33% per year (dose adjustment is not required).

Based on the population analysis of pharmacokinetics, the total Cl was higher in patients of the Negroid race, on average, by 20%.

Effect on efficiency. In the kidney and heart recipients for 6 months after transplantation, a relationship was established between the basal concentration of everolimus and the frequency of acute rejection and thrombocytopenia confirmed by biopsy.

Table

Kidney Transplantation
C0, ng / ml ≤3,4 3,5–4,5 4,6–5,7 5,8–7,7 7,8–15
Absence of rejection 68% 81% 86% 81% 91%
Thrombocytopenia (<100 • 109 / L) 10% 9% 7% 14% 17%
Heart transplantation
Ñ0, 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 (<75·109L) 5% 5% 6% 8% 9%

Indication of the drug Sertiñan

Prevention of rejection of kidney and heart transplant in adult recipients with low and medium immunological risk receiving basic immunosuppressive therapy with cyclosporin in the form of microemulsion and GCS.

Data on the use of the drug Sertican® in children and adolescents is not enough to recommend the use of the drug in this category of patients. However, there are limited data on the use of the drug in pediatrics for kidney transplantation.

Contraindications

Hypersensitivity to everolimus, sirolimus or other components of the drug.

Carefully:

Severe hepatic insufficiency (since the safety and efficacy of everolimus in patients with impaired liver function have not been studied - it is recommended to carefully monitor its concentration in the blood plasma);

Rare hereditary disorders associated with intolerance to galactose, severe lactase deficiency, or glucose-galactose malabsorption;

Children and adolescents (data on the use of the drug Sertican® is not enough to recommend the use of the drug in this category of patients). However, there are limited data on the use of the drug in pediatrics for kidney transplantation;

Simultaneous use of other drugs that have a negative effect on kidney function.

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.

Application in pregnancy and breastfeeding

Data on the use of the drug Sertican ® in pregnancy 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. Sertican® should not be used in pregnant women unless the expected benefit from therapy exceeds the potential risk to the fetus.

Women of childbearing age should be recommended to use effective methods of contraception during treatment with the drug Sertican® and within 8 weeks after the end of therapy.

It is not known whether everolimus is excreted in 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 Sertopic® should not breast-feed.

Side effects

Data on the incidence of adverse reactions were obtained during 3 clinical trials (combined data from 1199 patients). In these 3 randomized, double-blind, controlled, multicenter clinical trials (2 studies in patients with kidney transplantation de novo and 1 study in patients with de novo heart transplantation) in which the Sertican® was administered at a dose of 1.5 or 3 Mg / day for at least 12 months in combination with cyclosporin in the form of a microemulsion and GCS.

Also, data on the incidence of adverse reactions were obtained in 2 open trials in which the efficacy and safety of the use of the Sertican® dose 1.5 and 3 mg / day in combination with cyclosporine in a reduced dose in patients with kidney transplantation de novo was studied.

To determine the frequency of undesired reactions, the following criteria were used: very often (≥1 / 10); Often (≥1 / 100, <1/10); Sometimes (≥1 / 1000, <1/100); Rarely (≥1 / 10000, <1/1000); Very rarely (<1/10000).

The following are undesirable reactions, possibly or probably having a connection with the use of the drug Seretican®, which have been documented in Phase III clinical trials (kidney or heart transplantation).

Infectious diseases: often - viral, bacterial and fungal infections, sepsis; Sometimes - wound infection.

From the hemopoietic system and the lymphatic system: very often - leukopenia; Often - thrombocytopenia1, anemia1, coagulopathy, thrombotic thrombocytopenic purpura / hemolytic uremic syndrome; Sometimes hemolysis.

From the endocrine system: sometimes - hypogonadism in men (decrease in testosterone level, increase in LH level).

Metabolic disorders: very often - hypercholesterolemia, hyperlipidemia; Often hypertriglyceridemia.

From the side of the vascular system: often - increased blood pressure, lymphocele3, venous thrombosis.

From the respiratory system: often - pneumonia; Sometimes - interstitial lung disease, pulmonary alveolar proteinosis.

From the digestive system: often - abdominal pain, diarrhea, nausea, pancreatitis, vomiting.

From the hepatobiliary system: sometimes - hepatitis, violations of the liver, jaundice, increased levels of ALT, ACT, GGT.

From the skin and subcutaneous tissue: often - angioedema, acne, complications from the surgical wound; Sometimes - a rash.

From the musculoskeletal system: sometimes - myalgia.

From the urinary system: often - urinary tract infections; Sometimes - necrosis of the renal tubules, pyelonephritis.

Other: often - swelling, pain.

Note:

1, a dose-dependent effect was established or this phenomenon was observed much more often in patients receiving the drug at a dose of 3 mg / day.

2 for heart transplantation.

3 for kidney transplantation.

4 predominantly in patients taking concomitantly ACE inhibitors.

In controlled clinical trials in which patients were observed for at least 1 year, lymphoma or lymphoproliferative disease developed in 1.4% of patients receiving a Sertican® drug (1.5 or 3 mg / day) in combination with other immunosuppressants. Malignant skin lesions were recorded in 1.3% of patients, and other types of malignancy - in 1.2% of patients.

The occurrence of these adverse events may depend on the extent and duration of immunosuppressive therapy. In the main 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. The overall incidence of adverse events was lower with a reduced dose of cyclosporin in the form of a microemulsion.

The safety profile of the preparation Sertican® in studies with the use of the drug together with a reduced dose of cyclosporine was the same as in the 3 main studies where a standard dose of cyclosporine was administered. However, with the use of the drug Sertican® together with a reduced dose of cyclosporine, an increase in the concentration of creatinine in the blood plasma was noted less and a lower mean and median plasma creatinine concentration was observed than in other phase III studies.

With the use of m-TOR inhibitors, including the Sertican® preparation, lesions of the lung parenchyma were rarely seen, for example inflammation of the lung parenchyma (pneumonitis) and / or pulmonary fibrosis of non-infectious etiology, in isolated cases with a fatal outcome. In most cases, after the withdrawal of therapy with the drug Sertican® and / or the use of GCS, the disappearance of these undesirable reactions was noted.

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, preparations interacting with CYP3A4 and / or P-glycoprotein can influence the absorption and subsequent elimination of systemically absorbed everolimus. Combined use of the preparation Sertican® with strong inhibitors or inducers of CYP3A4 is not recommended. 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, potentially increasing plasma concentrations of drugs released with the participation of these enzymes. Therefore, care should be taken when using the Sertican simultaneously with the substrates CYP3A4 and CYP2D6, which have a narrow therapeutic index. All the in vivo interactions were conducted without the simultaneous use of cyclosporin.

Cyclosporin (inhibitor of CYP3A4 / P-glycoprotein). Bioavailability of everolimus significantly increased with the simultaneous use of cyclosporine. In a single dose study in healthy volunteers, cyclosporin in the form of a microemulsion (Sandimmun Neoral) increased the everolimus AUC by 168% (from 46 to 365%) and Cmax 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.

The clinical significance of the effect of the drug Seretican® on the pharmacokinetics of cyclosporine is minimal in patients with kidney and heart transplant who receive cyclosporin in the form of a microemulsion.

Rifampicin (inducer CYP3A4). In healthy volunteers who received previous therapy with multiple doses of rifampicin, with a subsequent application of the Sertican® preparation in a single dose, an almost 3-fold increase in Cl of everolimus was observed, and a decrease of Cmax by 58% and AUC by 63%. The combined use of Sertican with rifampicin is not recommended.

Atorvastatin (substrate CYP3A4) or pravastatin (P-glycoprotein substrate). When a single dose of the drug Sertican® with atorvastatin or pravastatin was administered to healthy volunteers, no clinically significant effect on the pharmacokinetics of atorvastatin, pravastatin, and everolimus, as well as the overall bioreactivity of HMG-CoA reductase in plasma was detected. However, these results cannot 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.

Another possible interaction. Moderate inhibitors of CYP3A4 and P-glycoprotein can increase the concentration of everolimus in the blood (for example, antifungal agents: fluconazole, macrolide antibiotics - erythromycin, CCB - verapamil, nicardipine, diltiazem, protease inhibitors - nelfinavir, indinavir, amprenavir).

CYP3A4 inductors can increase the metabolism of everolimus and decrease the concentration of everolimus in the blood (for example, St. John's wort, anticonvulsants - carbamazepine, phenobarbital, phenytoin; drugs for the treatment of HIV - efavirenz, nevirapine.)

Grapefruit and grapefruit juice affect the activity of cytochrome P450 and P-glycoprotein, so their use should be avoided against the background of the use of the drug Sertican®.

Vaccination. Immunosuppressants may influence the response during vaccination; Against the background of treatment with the drug Sertican®, vaccination may be less effective. Use of live vaccines should be avoided.

Dosing and Administration

Inside - or always with food, or always without it.

Adults. The recommended initial dose of the drug for patients with renal and cardiac transplants is 0.75 mg 2 times / day. The drug should be used as soon as possible after transplantation. The daily dose of the drug Sertican® is always divided into 2 doses. Sertican® is administered at the same time as cyclosporin in the form of a microemulsion. It may be necessary to adjust the dosage regimen of the drug Sertican® 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 frequency of cases of development of acute rejection, confirmed by biopsy, was higher in representatives of the Negroid race than in the rest. According to the limited information available, representatives of the Negroid race may need a higher dose of Sertican® to achieve the same effect as other patients receiving the drug at recommended adult dosages. Currently available data on efficacy and safety is not sufficient to provide specific recommendations on the use 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 adult patients.

Patients with impaired renal function. In patients with impaired renal function, dose adjustment is not required.

Application for violations of liver function. Patients with hepatic insufficiency should carefully monitor the basal concentration of everolimus in whole blood. In patients with mild or moderate hepatic impairment (grade A or B on the Child-Pough scale), the dose of the drug Seretican should be reduced approximately 2-fold compared with the average dose when there is a combination of 2 indicators listed below: bilirubin> 34 Μmol / L (> 2 mg / dL), albumin <35 g / l (<3.5 g / dl), MHO (INR, International Normalized Ratio)> 1.3 (prolongation IV> 4 s). Further titration of the dose is carried out based on the data of therapeutic monitoring. In patients with severe hepatic insufficiency (class C on the scale Child-Pough) everolimus has not been studied.

Therapeutic monitoring. It is recommended to regularly monitor the therapeutic concentration of everolimus in whole blood. Based on the analysis of exposure-efficiency and exposure-safety, it was found that in patients with C0> 3 ng / ml, the incidence of acute rejection of both kidney and heart, confirmed by biopsy, was lower than in patients with C0 <3 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. The concentrations of everolimus were determined by chromatography.

It is particularly important to monitor the concentrations of everolimus in the blood in patients with hepatic insufficiency during the simultaneous use of strong inducers and inhibitors of 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 preparation Sertican®, based on the C0 values of everolimus, determined more than 4-5 days after the previous dose change. Since cyclosporine interacts with everolimus, a decrease in the concentration of the latter is possible, if the concentration of cyclosporine is significantly reduced (C0 <50 ng / ml).

Recommendations on the dosage regimen of cyclosporine in combination therapy with the Sertican® in patients after kidney transplantation

The drug Sertican® should not be used for a long time with cyclosporine in a full dose. Reducing the dose of cyclosporine in patients after kidney transplantation who received the Sertican® preparation 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 taking the drug (C0 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 (C0) is> 3 ng / ml.

Recommendations on the dosage regimen of cyclosporine in combination therapy with the Sertican® in patients after heart transplantation

For patients after heart transplantation in the supporting phase, a dose of cyclosporine should be reduced one month after transplantation in order to improve kidney function. With progression of renal dysfunction, or if the calculated Cl creatinine value is <60 ml / min, correction of the therapy regimen is necessary. Based on the data obtained in clinical trials, it has been established that in the appointment of everolimus in this category of patients, the target concentrations of cyclosporin in plasma according to C0 monitoring data should be as follows: 200-300 ng / ml to the 1st 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 (C0) is equal to or higher than 3 ng / ml.

In heart transplantation, there are limited data on the dosing of the drug Sertican® with C0 cyclosporine 50-100 ng / mg at 12 months after transplantation.

Instructions for the use of the drug in the form of tablets. Tablets should be taken whole, not crushed before use; To wash down a glass of water.

Instructions for the use of the drug in the form of tablets are dispersible. Patients who cannot swallow tablets are prescribed Sertican® in the form of dispersible tablets, from which the dispersion is prepared (suspended particulate matter in water).

Admission with an oral syringe of 10 ml. When taking dispersible tablets, an oral syringe can be used. To do this, place the dispersible tablets in a syringe. The maximum amount of Sertican®, from which a dispersion with a water volume of 10 ml (10 ml syringe) can be prepared, is 1.25 mg. Then add water to the mark of 5 ml, wait 90 s, while slightly shaking the syringe. After the dispersion is formed, the contents of the syringe are injected directly into the mouth. Then, rinse the syringe with 5 ml of water and put the contents into the mouth. After this, drink 10-100 ml of water.

Reception from a plastic cup. When using dispersible tablets, a plastic cup can be used. To do this, place dispersible tablets of the drug Sertican® in a plastic cup containing approximately 25 ml of water. The maximum amount of the Sertican® preparation from which a dispersion with a water volume of 25 ml can be prepared is 1.5 mg. Next, leave the dish for about 2 minutes to form a dispersion; Before use, shake the contents of the cup to allow the tablets to dissolve. Then immediately rinse the cup, adding 25 ml of water, and completely drink the contents.

Introduction through a nasogastric tube. When receiving dispersible tablets, a nasogastric tube can be used. To do this, place dispersible tablets of the drug Sertican® in a small plastic medical glass containing 10 ml of water. Wait 90 seconds, gently rotating the glass. Then it is necessary to dial the dispersion in a syringe and slowly (for 40 s) through a nasogastric tube. Then rinse the glass and syringe 3 times, collecting 5 ml of water, and enter through the probe. After this, flush the probe with 10 ml of water. After the administration of the drug Sertican®, the nasogastric tube should be clamped for at least 30 minutes.

If cyclosporine in the form of a microemulsion is also injected through a nasogastric tube, this should be done before the Sertopic® is administered. Do not mix these 2 drugs.

Overdose

In experimental studies, it has been shown that everolimus has a low acute toxicity potential. After ingestion of the drug at a dose of 2000 mg / kg, no single deaths or severe toxicity were 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, acceptable tolerability of the drug was noted.

Treatment: In all cases of overdose, general supportive measures should be initiated.

Special instructions

Treatment with Sertican® should be initiated and conducted only by physicians with experience of immunosuppressive therapy after organ transplantation and who have the ability to monitor the concentration of everolimus in whole blood.

In clinical trials, the preparation of Sertican® was used simultaneously with cyclosporine in the form of a microemulsion, basiliximab and GCS. The use of the drug Sertican® in combination with other immunosuppressive agents has not been adequately studied.

The use of the drug in patients with high immunological risk is insufficiently studied.

It is not recommended that the use of the drug Seretican with strong inhibitors of CYP3A4 (eg ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir) and inducers (eg rifampicin, rifabutin) be combined unless the expected benefit of this 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 CYP3A4 and after their withdrawal.

In patients receiving therapy with immunosuppressive agents, 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 identify skin lesions, recommend minimizing the effects of UV radiation, sunlight and use appropriate sunscreen.

Hyperimmunosuppression, incl. And when using therapy schemes based on the drug, Sertican® predisposes to the development of infections, especially those caused by opportunistic pathogens.

There are reports of the development of fatal infections and sepsis with the use of the drug Sertican. In clinical trials, the preparation Sertican® was used to prevent the development of pneumonia caused by Pneumocystis jiroveci (carini) for 12 months after transplantation.

In patients with persistently persisting clinical picture of pneumonia with ineffective antibiotic therapy and exclusion of infectious, neoplastic and other non-drug-related processes, interstitial lung involvement should be suspected.

Prevention of the development of cytomegalovirus infection was recommended within 3 months after transplantation, especially in patients with an increased risk of developing this infection.

The combined use of the preparation Sertican® with cyclosporin in the form of a microemulsion in patients after transplantation was associated with an increase in serum cholesterol and triglycerides, which may require appropriate treatment. Patients receiving Sertican® should be monitored for hyperlipidemia and, if necessary, treated with lipid-lowering medications and prescribed a suitable corrective diet. It is necessary to assess the risk / benefit ratio for patients who have been diagnosed with hyperlipidemia prior to initiating therapy with immunosuppressive agents, including the Sertican® preparation. Also, the risk / benefit ratio of continued therapy with the Sertican® in patients with severe refractory hyperlipidemia should be assessed.

Patients receiving HMG-CoA reductase inhibitors and / or fibrates should be monitored for adverse events caused by the above drugs.

Influence on the ability to drive vehicles and work with mechanisms. Studies of the effect of the drug Sertican® on the ability to drive and work with mechanisms have not been carried out.

Release form

Tablets 0.25 mg. 10 tab. In the blister PA / Alum. / PVC. By 5, b, 10 and 25 blisters are placed in a cardboard box.

Tablets 0.5 mg. 10 tab. In the blister PA / Alum. / PVC. For 5, 6, 10 and 25 blisters are placed in a cardboard box.

Tablets 0,75mg. 10 tab. In the blister PA / Alum. / PVC. For 5, 6, 10 and 25 blisters are placed in a cardboard box.

Tablets 1 mg. 10 tab. In the blister PA / Alum. / PVC. For 5, 6, 10 and 25 blisters are placed in a cardboard box.

Tablets are dispersible, 0.25 mg; 0.5 mg; 0,75mg; 1 mg. 10 tab. In the blister PA / Alum. / PVC. By 5, b, 10 and 25 blisters are placed in a cardboard box.

Manufacturer

Novartis Pharma AG, Switzerland ..

Produced

Novartis Pharma Stein AG, Switzerland.

Lichtstraße, 35, 4056, Basel, Switzerland.

Novartis Pharma AG, Switzerland.

Manufactured by Novartis Pharma Stein AG, Switzerland.

Lichtstrasse 35, 4056 Basel, Switzerland.

Conditions of supply of pharmacies

On prescription.

Storage conditions of the drug Sertiñan

In a dry, the dark place at a temperature of no higher than 30 ° C.

Keep out of the reach of children.

Shelf life of the drug Sertiñan

3 years.

Do not use after the expiry date printed on the package.

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