Sertican, tablets 500 mcg 60 pcs

The active ingredient of Sertican^®, everolimus, is a proliferative signal inhibitor. Everolimus has an immunosuppressive effect by inhibiting antigen-activated T-cell proliferation and, consequently, clonal expansion induced by specific T-cell ILs (such as IL-2 and IL-15). Everolimus inhibits the intracellular signaling pathway that normally leads to cell proliferation triggered by the binding of these T-cell growth factors to their respective receptors. Blockade of this signaling by everolimus results in arrest of cell division at 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, growth factor-stimulated p70 S6 kinase phosphorylation is inhibited. Since phosphorylation of p70 S6 kinase is under the control of FRAP (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; disruption of FRAP function thus explains the cell cycle arrest induced by everolimus. Everolimus has, therefore, a different mechanism of action than cyclosporine. In preclinical allograft models, the combination of everolimus with cyclosporine has been shown to be more effective than the isolated use of each.

The effect of everolimus is not limited to its effect on T cells. It inhibits growth factor-stimulated proliferation of both hematopoietic and non-hematopoietic cells (e.g. smooth muscle cells). Growth factor-stimulated vascular smooth muscle cell proliferation, which is triggered by endothelial cell damage and leads to neointima formation, plays a key role in the pathogenesis of chronic rejection.

In experimental studies, inhibition of neointima formation has been shown in rats with aortic allografts.

Pharmacokinetics

Intake. After oral administration, C_max is reached after 1-2 h. In post-transplant patients, the blood concentration of everolimus is proportional to the dose in the dose range of 0.25 to 15 mg. Based on the AUC, the relative bioavailability of dispersible tablets compared to tablets is 90%.

The effect of food: C_max and AUC of everolimus were decreased by 60 and 16%, respectively, when tablets were taken with very fatty foods. To minimize variability, Sertican^® should be taken either concomitantly with or without food.

Distribution. The ratio of Everolimus blood concentration to its plasma concentration ranges from 17% to 73% and is dependent on concentration values between 5 and 5000 ng/ml. In healthy volunteers and patients with moderate hepatic impairment, binding to plasma proteins is approximately 74%. V_SS in the end 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 metabolic pathways identified in humans were monohydroxylation and O-dealkylation. The two major metabolites are formed by hydrolysis of the cyclic lactone. Neither of them has significant immunosuppressive activity. Everolimus is mainly found in the systemic bloodstream.

Evacuation. After administering a single dose of radioactively labeled everolimus to post-transplant patients receiving cyclosporine, most (80%) of the radioactivity was detected in the feces, with a small amount (5%) excreted in the urine. No unchanged substance was detected in either urine or feces.

Pharmacokinetics in equilibrium state

Pharmacokinetics in renal and cardiac transplant patients receiving everolimus 2 times daily simultaneously with cyclosporine in microemulsion form were comparable. Equilibrium was reached on day 4 with cumulation in the blood in concentrations that were 2-3 times higher than blood concentrations after the first dose. After drug administration, T_max is 1-2 h. When taking the drug in doses of 0.75 and 1.5 mg twice daily, the mean C_max values are (11.1±4.6) ng/mL and (20.3±8.0) ng/mL, the mean AUC values are (75±31) ng×h/mL and (131±59) ng×h/mL respectively. When administered at doses of 0.75 and 1.5 mg twice daily, the C₀ of everolimus in blood averaged (4.1±2.1) ng/m or (7.1±4.6) ng/mL, respectively (C₀ is the basal concentration determined in the morning before the next dose). Everolimus exposure remained stable at all times during the first year after transplantation. C₀ was highly correlated with AUC with a correlation coefficient ranging between 0.86 and 0.94. Based on pharmacokinetics analysis in post-transplant patients, total clearance is 8.8 L/h (27% variation), central apparent V_SS is 110 L (36% variation). T_1/2 is (28±7) h.

Pharmacokinetics in special clinical cases

Hepatic disorders.In 8 patients with moderately severe hepatic impairment (Child-Pough class B) the AUC of everolimus was increased approximately 2-fold compared to that of 8 healthy volunteers. AUC correlated positively with serum bilirubin concentration and increased PV and correlated negatively with serum albumin concentration. If bilirubin concentration was >34 μmol/L, PV was >1.3 INR (prolongation >4 sec) and/or albumin concentration was

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

Pediatrics. Cl everolimus increased in a linear relationship with patient age (1 to 16 years), body surface area (0.49-1.92 m²), and body weight (11-77 kg). At equilibrium, Cl was (10.2±3.0) L/h/m², T_1/2 was (30±11) h.

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

Adult patients. Adult patients aged 16 to 70 years showed a 0.33% decrease in everolimus clearance per year (no dose adjustment required).

Based on a population-based pharmacokinetic analysis, total Cl was higher in non-Hispanic patients, on average, by 20%.

The effect on efficacy. In kidney and heart recipients at 6 months after transplantation, there was an association between the basal concentration of everolimus and the incidence of biopsy-confirmed acute rejection and thrombocytopenia.

Table

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Indications

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

Pharmacological effect

The active substance of the drug Certican® – everolimus – is an inhibitor of the proliferative signal. Everolimus exerts its immunosuppressive effect by inhibiting antigen-activated T cell proliferation and, accordingly, clonal expansion caused by specific T cell ILs (eg IL-2 and IL-15). Everolimus inhibits the intracellular signaling pathway that normally leads to cell proliferation triggered by the binding of these T cell growth factors to their corresponding receptors. Blockade of this signal by everolimus stops cell division at 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, growth factor-stimulated p70 S6 kinase phosphorylation is inhibited. Because p70 S6 kinase phosphorylation is under the control of FRAP (called m-TOR), these data suggest that the everolimus-FCBP-12 complex binds to FRAP. FRAP is a key regulatory protein that controls cellular metabolism, growth and proliferation; disruption of FRAP function thus explains the cell cycle arrest induced by everolimus. Everolimus therefore has a different mechanism of action from cyclosporine. In preclinical allotransplantation models, the combination of everolimus and cyclosporine has been shown to be more effective than using either alone.

The effect of everolimus is not limited to its effect on T cells. It inhibits growth factor-stimulated proliferation of both hematopoietic and non-hematopoietic cells (eg smooth muscle cells). Growth factor-stimulated 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.

Experimental studies have shown inhibition of neointimal formation in rats with aortic allograft.

Pharmacokinetics

Suction. After oral administration, Cmax is reached within 1–2 hours. In transplant patients, the concentration of everolimus in the blood is proportional to the dose in the dose range from 0.25 to 15 mg. Based on AUC, the relative bioavailability of dispersible tablets compared to tablets is 90%.

Effect of food: Everolimus Cmax and AUC were decreased by 60 and 16%, respectively, when the tablets were taken with a very fatty meal. To minimize variability, Certican® should be taken either with or without food.

Distribution. The ratio of everolimus concentration in the blood to its plasma concentration ranges from 17 to 73% and depends on concentration values ​​ranging from 5 to 5000 ng/ml. In healthy volunteers and patients with moderate liver dysfunction, plasma protein binding is approximately 74%. VSS in the final phase in patients after kidney transplantation who are on maintenance therapy is (342±107) l.

Metabolism. Everolimus is a substrate of CYP3A4 and P-glycoprotein. The main metabolic pathways identified in humans were monohydroxylation and O-dealkylation. Two major metabolites are formed by hydrolysis of the cyclic lactone. None of them have significant immunosuppressive activity. Everolimus is found mainly in the systemic circulation.

Excretion. Following administration of a single dose of radiolabeled everolimus to transplant patients receiving cyclosporine, the majority (80%) of the radioactivity was detected in the feces, with a small amount (5%) excreted in the urine. The unchanged substance was not detected in either urine or feces.

Pharmacokinetics at steady state

The pharmacokinetics in patients with kidney and heart transplants receiving everolimus 2 times a day simultaneously with cyclosporine in the form of a microemulsion were comparable. The equilibrium state was reached on the 4th day with accumulation in the blood in concentrations that were 2–3 times higher than the concentrations in the blood after the first dose. After taking the drug, Tmax is 1–2 hours. When taking the drug in doses of 0.75 and 1.5 mg 2 times a day, the average Cmax values ​​are (11.1±4.6) ng/ml and (20.3±8.0) ng/ml, the average AUC values ​​are (75±31) ng×h/ml and (131±59) ng×h/ml, respectively. When taking the drug in doses of 0.75 and 1.5 mg 2 times a day, the C0 of everolimus in the blood is, on average, (4.1 ± 2.1) ng/m or (7.1 ± 4.6) ng/ml, respectively (C0 is the basal concentration determined in the morning before taking the next dose). Everolimus exposure remains stable throughout the first year after transplantation. CO was highly correlated with AUC with correlation coefficients ranging between 0.86 and 0.94. Based on pharmacokinetic analysis in transplant patients, the total clearance is 8.8 L/h (range: 27%) and the central apparent VSS is 110 L (range: 36%). T1/2 is (28±7) hours.

Pharmacokinetics in special clinical situations

Liver dysfunction: In 8 patients with moderately severe liver dysfunction (Child-Pough class B), the AUC of everolimus increased approximately 2-fold compared with that in 8 healthy volunteers. AUC was positively correlated with serum bilirubin concentration and PT increase and negatively correlated with serum albumin concentration. If the bilirubin concentration was >34 µmol/L, the PT was >1.3 INR (prolongation >4 sec) and/or the albumin concentration was

Renal dysfunction. Post-transplant renal failure (creatinine clearance 11–107 ml/min) did not affect the pharmacokinetic parameters of everolimus.

Pediatrics. Everolimus Cl increased linearly with patient age (1 to 16 years), body surface area (0.49–1.92 m2), and body weight (11–77 kg). At equilibrium, Cl was (10.2±3.0) l/h/m2, T1/2 – (30±11) h.

Nineteen de novo patients after kidney transplantation aged from 1 to 16 years received the drug Certican® in the form of dispersible tablets 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 AUC of everolimus was (87±27) ng×h/ml, and was similar to that in adults receiving 0.75 mg 2 times a day. At steady state, the basal concentration was (4.4 ± 1.7) ng/ml.

Adult patients. In adult patients aged 16 to 70 years, a decrease in everolimus clearance of 0.33% per year was observed (no dose adjustment required).

Based on a population pharmacokinetic analysis, total Cl was higher in black patients by an average of 20%.

Impact on efficiency. In kidney and heart recipients within 6 months after transplantation, an association was found between basal everolimus concentrations and the incidence of biopsy-proven acute rejection and thrombocytopenia.

Table

Kidney transplant

C0, ng/ml
≤3.4
3.5–4.5
4.6–5.7
5.8–7.7
7.8–15
No rejection
68%
81%
86%
81%
91%
Thrombocytopenia (9/l)
10%
9%
7%
14%
17%
Heart transplant
C0, ng/ml
≤3.5
3.6–5.3
5.4–7.3
7.4–10.2
10.3–21.8
No rejection
65%
69%
80%
85%
85%
Thrombocytopenia (9/l)
5%
5%
6%
8%
9%

Special instructions

Treatment with Certican® should only be initiated and administered by physicians experienced in administering immunosuppressive therapy after organ transplantation and who are able to monitor the concentration of everolimus in whole blood.

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

The use of the drug in patients with high immunological risk has not been sufficiently studied.

Concomitant use of Certican® with strong CYP3A4 inhibitors (for example, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir) and inducers (for example, rifampicin, rifabutin) is not recommended, unless the expected benefit of such therapy outweighs the potential risk.

It is recommended to monitor everolimus whole blood concentrations during concomitant use with CYP3A4 inducers or inhibitors and after their discontinuation.

Patients receiving therapy with immunosuppressive drugs, including Certican®, have an increased risk of developing lymphomas and other malignant diseases, especially of the skin. The absolute risk is related to the duration and intensity of immunosuppression rather than to the use of a specific drug. Patients should be regularly monitored for skin lesions, recommended to minimize exposure to UV radiation, sunlight, and use of appropriate sunscreens.

Hyperimmunosuppression, incl. and when using treatment regimens based on the drug Certican® predisposes to the development of infections, especially those caused by opportunistic pathogens.

There are reports of the development of fatal infections and sepsis when using the drug Certican®. In clinical studies, Certican® was used to prevent the development of pneumonia caused by Pneumocystis jiroveci (carini) for 12 months after transplantation.

In patients with a persistent clinical picture of pneumonia in the absence of antibiotic therapy and the exclusion of infectious, neoplastic and other processes not related to the use of drugs, interstitial lung disease should be suspected.

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

The combined use of Certican® with cyclosporine in the form of a microemulsion in patients after transplantation has been associated with an increase in serum cholesterol and triglycerides, which may require appropriate treatment. Patients receiving Certican® should be monitored for hyperlipidemia and, if necessary, treated with lipid-lowering agents and prescribed an appropriate corrective diet. It is necessary to assess the risk/benefit ratio for patients who have hyperlipidemia before starting therapy with immunosuppressive drugs, including Certican®. The risk/benefit ratio of continuing therapy with Certican® in patients with severe refractory hyperlipidemia should also be assessed.

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

Impact on the ability to drive vehicles and operate machinery. Studies of the effect of the drug Certican® on the ability to drive and operate machinery have not been conducted.

Active ingredient

Everolimus

Composition

active substance:

everolimus 50 mcg

Pregnancy

There are no data on the use of Certican® during pregnancy.

Experimental studies have shown toxic effects on reproduction, including embryotoxicity and fetotoxicity. It is unknown whether there is a potential risk to humans. Certican® should not be used in pregnant women unless the expected benefit of therapy outweighs the potential risk to the fetus.

Women of childbearing potential should be advised to use effective methods of contraception during treatment with Certican® and for 8 weeks after the end of therapy.

It is not known whether everolimus is excreted in human breast milk.

Experimental studies have shown that everolimus and/or its metabolites are rapidly excreted into the milk of lactating rats. Therefore, women receiving Certican® should not breastfeed.

Contraindications

Hypersensitivity to everolimus, sirolimus or other components of Certican.

Side Effects

Listed below are adverse reactions that may or may be related to the use of Certican®, which were reported in phase III clinical studies (kidney or heart transplantation).

Infectious diseases: often – viral, bacterial and fungal infections, sepsis; sometimes – wound infection.

From the hematopoietic and lymphatic systems: very often – leukopenia1; often – thrombocytopenia1, anemia1, coagulopathy, thrombotic thrombocytopenic purpura/hemolytic uremic syndrome; sometimes – hemolysis.

From the endocrine system: sometimes – hypogonadism in men (decreased testosterone levels, increased LH levels).

Metabolic disorders: very often – hypercholesterolemia, hyperlipidemia; often – hypertriglyceridemia.

From 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, liver dysfunction, jaundice, increased levels of ALT, AST, GGT.

From the skin and subcutaneous tissue: often – angioedema4, 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 significantly 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 concomitant ACE inhibitors.

In controlled clinical studies in which patients were followed for at least 1 year, lymphoma or lymphoproliferative disease developed in 1.4% of patients receiving Certican® (1.5 or 3 mg/day) in combination with other immunosuppressants. Skin malignancies were reported 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 degree and duration of immunosuppressive therapy. In the main studies, increases in serum creatinine concentrations were observed more frequently in patients receiving Certican® in combination with full dose cyclosporine microemulsion than in control patients. The overall incidence of adverse events was lower with a reduced dose of cyclosporine microemulsion.

The safety profile of Certican® in studies using the drug together with a reduced dose of cyclosporine was the same as in 3 main studies where a standard dose of cyclosporine was prescribed. However, when Certican® was used together with a reduced dose of cyclosporine, increases in plasma creatinine concentrations were observed less frequently and lower mean and median plasma creatinine concentrations were observed than in other phase III studies.

When using m-TOR inhibitors, including the drug Certican®, damage to the lung parenchyma was rarely observed, 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 discontinuation of therapy with Certican® and/or administration of GCS, the disappearance of these adverse reactions was noted.

Interaction

Metabolized with the participation of the CYP3A4 isoenzyme, it is a substrate for the P-glycoprotein carrier protein; therefore, use with potent inhibitors or inducers of CYP3A4 is not recommended. P-glycoprotein inhibitors may reduce the release of everolimus from intestinal cells and increase its serum concentrations.

Everolimus was a competitive inhibitor of CYP3A4 and CYP2D6, potentially increasing the concentrations of drugs metabolized by these enzymes. Caution should be exercised when everolimus is coadministered with CYP3A4 and CYP2D6 substrates, which have a narrow therapeutic index.

The bioavailability of everolimus is significantly increased by concomitant use of cyclosporine (CYP3A4/P-glycoprotein inhibitor). Cyclosporine in the form of a microemulsion increases the AUC of everolimus by 168% (46-365%) and Cmax by 82% (25-158%) compared with the use of everolimus alone. If the dose of cyclosporine is changed, the dose of everolimus may need to be adjusted. The clinical significance of the effect of everolimus on the pharmacokinetics of cyclosporine is minimal in kidney and heart transplant patients receiving microemulsion cyclosporine.

The use of everolimus after multiple doses of rifampicin (CYP3A4 inducer) increases the clearance of everolimus by 3 times, reduces Cmax by 58% and AUC by 63%. The combined use of everolimus with rifampicin is not recommended. Taking a single dose of everolimus with atorvastatin (CYP3A4 substrate) or pravastatin (P-glycoprotein substrate) does not have a clinical effect on the pharmacokinetics of atorvastatin, pravastatin, everolimus or the overall bioreactivity of HMG-CoA reductase in plasma. However, these results do not take into account the effect of other HMG-CoA reductase inhibitors.

Patients receiving HMG-CoA reductase inhibitors should be monitored for the development of rhabdomyolysis and other adverse events. Moderate inhibitors of CYP3A4 and P-glycoprotein (fluconazole, erythromycin, verapamil, nicardipine, diltiazem, nelfinavir, indinavir, amprenavir) may increase the concentration of everolimus in the blood.

Inducers of CYP3A4 (St. John’s wort, carbamazepine, phenobarbital, phenytoin, efavirenz, nevirapine) may increase the metabolism of everolimus and reduce its concentration in the blood. Grapefruit juice affects the activity of cytochrome P450 and P-glycoprotein, so its simultaneous use with everolimus should be avoided. Vaccination may be less effective during treatment with everolimus. The use of live vaccines should be avoided.

Overdose

Everolimus has been shown to have a low potential for acute toxicity in experimental studies. After oral administration of the drug at a dose of 2000 mg/kg, no deaths or severe toxicity were observed in mice and rats (range control).

Reports of human overdose are very limited. There is only one case of accidental ingestion of 1.5 mg everolimus by a child aged 2 years, with no adverse events observed. With a single oral dose of up to 25 mg, patients after transplantation showed acceptable tolerability of the drug.

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

Storage conditions

In a dry place, protected from light, at a temperature not exceeding 30 °C

Shelf life

3 years

Manufacturer

Novartis Neva LLC, Russia