Sertikan - instructions for use, reviews, analogs and formulations (0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg and 1 mg tablets) medications to prevent kidney and heart transplant rejection in adults, children and during pregnancy. Composition

In this article, you can read the instructions for using the drug Sertikan. There are reviews of visitors to the site - consumers of this medication, as well as opinions of doctors of experts on the use of Certicana in their practice. A big request is to actively add their feedback on the drug: the medicine helped or did not help get rid of the disease, which were observed complications and side effects, possibly not declared by the manufacturer in the annotation. Analogues of Sertikan in the presence of existing structural analogues. Use to prevent kidney and heart transplant rejection in adults, children, as well as during pregnancy and lactation. Composition of the preparation.

Sertikan - immunosuppressive drug. Everolimus (the active substance of the drug Sertikan) is an inhibitor of the proliferative signal. Everolimus has an immunosuppressive effect by inhibiting antigen-activated T cell proliferation and, accordingly, clonal expansion caused by specific T-cell interleukins, for example interleukin-2 and interleukin-15. Everolimus inhibits the intracellular signaling pathway, which normally leads to cell proliferation triggered by the binding of these growth factors of T cells to the corresponding receptors. The blockade of this signal by Sertikan leads to a stop of 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 that Controls cellular metabolism, growth and proliferation. The violation of the function of FRAP, thus, explains the arrest of the cell cycle caused by everolimus.The sertikan therefore has a mechanism different from the cyclosporin. In preclinical models of allotransplantation, a higher efficacy of the combination of everolimus with cyclosporin was shown than with the isolated use of each of them.

The effect of everolimus is not limited to the effect on T-cells. It inhibits the proliferation of both hematopoietic and nonhematopoietic cells (for example, smooth muscle cells) 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.

Composition

Everolimus + auxiliary substances.

Pharmacokinetics

After oral administration, the maximum concentration of Cercan in the blood is reached after 1-2 hours. In healthy volunteers and patients with moderate impairment of liver function, binding to plasma proteins is approximately 74%. Everolimus is a substrate of CYP3A4 and P-glycoprotein.The main ways of metabolism, found in humans, were monohydroxylation and O-dealkylation. Two major metabolites are formed by hydrolysis of cyclic lactone. None of them has significant immunosuppressive activity. In the systemic blood stream is mainly everolimus. After administration of a single dose of radiolabeled everolimus to patients after transplantation receiving cyclosporin, most (80%) of the 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 special clinical cases

In 8 patients with moderate hepatic impairment (class B on the Child-Pugh scale), the area under the pharmacokinetic curve (AUC) of everolimus increased approximately 2-fold compared to those in 8 healthy volunteers. The AUC index positively correlated with the serum bilirubin concentration and the prothrombin time increase and negatively correlated with the serum albumin concentration. The effect of severe hepatic insufficiency (class C on the Child-Pugh scale) on AUC has not been studied,but, probably, it is the same or more pronounced than the impact of moderate hepatic insufficiency.

Post-transplantation renal failure (creatinine clearance 11-107 ml per minute) did not affect the pharmacokinetic parameters of everolimus.

The clearance of everolimus increased linearly depending 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 adult patients aged 16 to 70 years, a decrease in the clearance of everolimus by 0.33% per year was observed. Correction of the dose is not required.

Indications

• prevention of kidney and heart transplant rejection in adult recipients with low and medium immunological risk receiving basic immunosuppressive therapy with cyclosporin in the form of a microemulsion and glucocorticosteroids.

Forms of release

Tablets 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg and 1 mg.

Instructions for use and dosing regimen

The drug is taken orally. Tablets should be taken whole, not crushed before use, washed down with a glass of water.

Patients who can not swallow tablets are prescribed Serticane in the form of dispersible tablets, from which a dispersion is prepared (small solid particles in water). When taking dispersible tablets, an oral syringe can be used.To do this, place the dispersible tablets in a syringe. The maximum amount of Serticane 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 seconds, 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 by typing 5 ml of water, and insert the contents into the mouth. After this, the patient should drink 10-100 ml of water.

When using dispersible tablets, a plastic cup can be used. To do this, place the dispersible Serticine tablets in a plastic cup containing approximately 25 ml of water. The maximum amount of Serticane 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.

When receiving dispersible tablets, a nasogastric tube can be used.To do this, place the dispersed Serticana tablets 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 (within 40 seconds) enter through a nasogastric tube. Then you should rinse the glass (and syringe) 3 times, collecting 5 ml of water, and enter through the probe. After this, wash the probe with 10 ml of water. After the introduction of Serticana probe should be clamped for at least 30 minutes.

If cyclosporin in the form of a microemulsion is also injected through a nasogastric tube, this should be done before the introduction of the Cercan. Do not mix these two drugs.

The recommended initial dose of the drug for adult patients with renal and cardiac transplants is 0.75 mg twice a day. The drug should be used as soon as possible after transplantation. The daily dose of Sertican is always divided into 2 doses; the drug is taken or always along with food, or always without it. The sericant is taken at the same time as cyclosporin in the form of a microemulsion. It may be necessary to correct the dosage regimen of Sertikan taking into account the achieved concentrations in the blood plasma, tolerance, 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.

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 available limited information, representatives of the Negroid race may require a higher dose of Certicana to achieve the same effect as other patients receiving the drug at recommended adult doses. Currently available data on efficacy and safety is not enough to provide specific recommendations on the use of everolimus in representatives of the Negroid race.

The clinical experience of using Certicana in patients over the age of 65 is limited. However, there are no clear differences in the pharmacokinetics of everolimus in patients over 65-70 years of age compared with younger adults.

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

In patients with hepatic insufficiency should carefully monitor the basal concentration of everolimus in whole blood. In patients with mild or moderate hepatic insufficiency (grade A or B on the Child-Pugh scale), the dose of Sertican should be reduced approximately 2-fold compared with the average dose when there is a combination of two of the indicators listed below: bilirubin> 34 μmol / l (more than 2 mg / dl), albumin less than 35 g / l (less than 3.5 g / dL), prothrombin time greater than 1.3 INR (prolongation more than 4 seconds). 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 Child-Pugh scale) everolimus has not been studied.

Therapeutic monitoring

It is recommended to regularly monitor the therapeutic concentration of everolimus in whole blood. 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.

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

The sericant should not be used for a long time with cyclosporine in a full dose. Reducing the dose of cyclosporine in patients after renal transplantation who received Sericane resulted in an improvement in renal function. Reduction of the dose of cyclosporine should be started 1 month after transplantation.

It is very important that in the early period after transplantation the concentrations of everolimus and cyclosporine do not decrease below the therapeutic range, in order to minimize the risk of lack of effect.

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

For patients after heart transplantation in the supporting phase, a dose of cyclosporine should be reduced to improve kidney function. With progression of renal dysfunction, or if the estimated creatinine clearance is less than 60 ml per minute, treatment regimens should be adjusted based on data from clinical trials.

Side effect

• leukopenia, thrombocytopenia, anemia, coagulopathy;
• thrombotic thrombocytopenic purpura;
• hemolytic uremic syndrome;
• hemolysis;
• hypogonadism in men (decreased testosterone, increased level of luteinizing hormone);
• hypercholesterolemia, hyperlipidemia, hypertriglyceridemia;
• pericardial effusion (accumulation of fluid in the pericardial cavity);
• increased blood pressure;
• lymphocele (accumulation of lymphatic fluid in the form of volumetric formations);
• venous thrombosis;
• Pleural effusion (accumulation of fluid in the pleural cavity);
• pneumonia (inflammation of the lung tissue);
• pneumonitis (inflammation of the vascular wall of the alveoli);
• abdominal pain, diarrhea, nausea, vomiting;
• hepatitis, liver dysfunction;
• jaundice;
• increase in blood levels of hepatic enzymes;
• angioedema;
• acne (acne on the skin);
• complications from a surgical wound;
• rash;
• Myalgia (pain in the muscle);
• urinary tract infections;
• necrosis of renal tubules;
• pyelonephritis (inflammation with a predominant lesion of the tubular kidney system);
• viral, bacterial and fungal infections;
• sepsis;
• wound infection;
• lymphoma or lymphoproliferative disease;
• malignant neoplasm of the skin.

Contraindications

• hypersensitivity to everolimus, sirolimus or other components of the drug.

Application in pregnancy and lactation

Data on the use of Serticana 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. Do not use Sertikan during pregnancy, 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 treatment with Sertican and within 8 weeks after the end of therapy.

It is not known whether everolimus is excreted in human milk. In experimental studies, it was shown that everolimus and / or its metabolites quickly penetrated the milk of lactating rats. Therefore, women who are receiving the Sertican should not breast-feed.

Use in children

Data on the use of Serticana 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 Certicana in pediatrics for kidney transplantation.

Application in elderly patients

The clinical experience of using Certicana in patients over the age of 65 is limited. However, there were no marked differences in the pharmacokinetics of everolimus compared to younger adults.

special instructions

The sericant should not be used in patients with rare hereditary disorders associated with intolerance to galactose, severe lactase deficiency, or glucose-galactose malabsorption.

Everolimus has not been studied in patients with severe hepatic insufficiency. It is recommended to carefully monitor the concentration of everolimus in the blood plasma in patients with impaired liver 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.Care should be taken when using other drugs that have a negative effect on kidney function.

Sertikanom Treatment should start and carry out only physicians with experience in immunosuppressive therapy following organ transplantation and who has the ability to monitor everolimus concentration in whole blood.

In clinical studies, Sertikan was used concomitantly with cyclosporine in the form of a microemulsion, basiliximab and glucocorticosteroids. The use of Certicana in combination with other immunosuppressive agents has not been adequately studied. The use of Serticane in patients with high immunological risk has not been adequately studied.

We do not recommend joint application Sertikana with strong inhibitors of CYP3A4 (eg, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir) and inducers (eg, rifampicin, rifabutin), except in cases where the expected benefits of such therapy outweighs the potential risk. It is recommended to monitor the concentrations of everolimus in whole blood when used simultaneously with inducers or inhibitors of CYP3A4 and after they are discontinued.

In patients receiving therapy with immunosuppressive agents, including Sertikan, the risk of developing lymphomas and other malignant diseases, especially of the skin, increases. 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 exposure to ultraviolet radiation, sunlight and use appropriate sunscreen.

Hypermunosuppression, including the use of Sertican-based therapies, predisposes to the development of infections, especially those caused by opportunistic pathogens. There are reports of the development of fatal infections and sepsis in the use of Certicana.

In clinical studies, Serticana prevented pneumonia caused by Pneumocystis carinii for 12 months after transplantation.

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 Certicana with cyclosporin in the form of a microemulsion in patients after transplantation was associated with an increase in serum cholesterol and triglyceride levels, which may require appropriate treatment. Patients receiving the Sertican should be monitored for hyperlipidemia and, if necessary, treated with lipid-lowering drugs and prescribe the appropriate corrective diet. It is necessary to assess the risk / benefit ratio for patients who have hyperlipidemia before the start of therapy with immunosuppressive agents, including Sertikan. Also, the risk / benefit ratio of continuation of Sertican therapy in patients with severe reflux hyperlipidemia should be assessed.

Patients receiving 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) inhibitors and / or fibrates should be monitored for the development of adverse events caused by the above medicines.

Drug Interactions

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. Therefore, the preparations interacting with CYP3A4 and / or P-glycoprotein can influence the absorption and subsequent elimination of systemically absorbed everolimus. Combined use of Serticana 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 applying the Certicana to the substrates CYP3A4 and CYP2D6, which have a narrow therapeutic index. All studies of in vivo interaction were conducted without simultaneous application of cyclosporine.

Bioavailability of everolimus significantly increased with simultaneous application of cyclosporine (inhibitor of CYP3A4 / P-glycoprotein). When changing the dose of cyclosporine, a correction of the dosage regimen of everolimus may be required.

The clinical significance of Certican's influence on the pharmacokinetics of cyclosporine is minimal in patients with kidney and heart transplant who receive cyclosporin in the form of a microemulsion.

In healthy volunteers who received previous therapy with multiple doses of rifampicin (inducer CYP3A4), with the subsequent application of Sertikan in a single dose, there was an almost 3-fold increase in the clearance of everolimus and a decrease in the maximum blood concentration by 58%. The combined use of Serticana with rifampicin is not recommended.

The administration of a single dose of Sertikan with Atorvastatin (substrate CYP3A4) or Pravastatin (substrate P-glycoprotein) in 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-Co A-reductase inhibitors should be monitored for rhabdomyolysis and other adverse events in accordance with the instructions for use of the aforementioned agents.

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

CYP3A4 inductors can increase the metabolism of everolimus and reduce the concentration of everolimus in the blood, for example, St. John's wort, anticonvulsants (carbamazepine, phenobarbital, phenytoin), drugs for the treatment of human immunodeficiency virus (efavirenz, nevirapine).

Grapefruit and grapefruit juice affect the activity of cytochrome P450 and P-glycoprotein, so avoid using them when using Sertikan.

Immunosuppressants can influence the response during vaccination. Against the background of Sertikan treatment, vaccination may be less effective. Use of live vaccines should be avoided.

Analogues of the drug Sertikan

Structural analogs for the active substance:

• The Athlete;
• Everolimus.

Analogues of the drug Sertikan for the pharmacological group (immunosuppressants):

• Abaggio;
• Advagraf;
• Azathioprine;
• Actemra;
• Antiliphosphine;
• Arava;
• Arresto;
• Artamine;
• Atgam;
• Benlist;
• Bianodine;
• Gilenia;
• The festival;
• Grafalon;
• Delagil;
• Zenapax;
• Ilaris;
• Immard;
• The Imnovid;
• Imuran;
• Consuprene;
• Xolar;
• Kuprenil;
• Leflish;
• Leflunomide;
• Lefomide;
• MabThera;
• Misept;
• Mayforth;
• The methodical;
• Mycophenolate sodium;
• Nulogix;
• Orgosporin;
• Orensia;
• Othello;
• Pantograph;
• Plaquenil;
• Prograph;
• Raleph;
• Rapamun;
• Raptiva;
• Redditus;
• Redesp;
• Remicade;
• Restasis;
• Rituximab;
• Sandimmun;
• Sandimmun;
• CellCent;
• Simponi;
• Simulect;
• Soliris;
• Stelara;
• Suprema;
• Tacrolimus;
• Tacrose;
• Tauredon;
• Teriflunomide;
• Tizabry;
• Timoglobulin;
• Timodepressin;
• Femoriks;
• Flammages;
• Humirah;
• Cyclosporin;
• Ecological;
• Elafra;
• Enbrel;
• Antivio;
• Yaqurinus.

Surgeon's doctor's opinion

Although I am working in the surgical department of a large clinic, I hardly ever have to prescribe my Sertikan drug to my patients. This is a very specific immunosuppressant that is used exclusively in transplantology to prevent graft rejection after transplantation to a diseased kidney or heart. And appoint it can only those doctors who have experience of conducting immunosuppressive therapy precisely after operations on organ transplantation.In addition, the medical institution should have the means to continuously monitor the concentration of everolimus in whole blood.

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