Certican® [Everolimus]

Brand Novartis

In stock 1909 Items

Available since: 2019-09-19

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Clinical Pharmacology

The active substance of the drug Certain^® - everolimus is a proliferative signal inhibitor. Everolimus has an immunosuppressive effect by inhibiting the antigen-activated proliferation of T-cells and, accordingly, clonal expansion caused by specific IL-T cells (for example, 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 by everolimus leads to stopping cell division at stage G₁ cell cycle.

At the molecular level, everolimus forms a complex with the cytoplasmic protein FKBP-12. In the presence of everolimus, inhibition of phosphorylation of p70 S6 kinase stimulated by growth factor occurs. Since phosphorylation of p70 S6 kinase is under the control of FRAP (the so-called m-TOR), these data suggest that the everolimus-FKVR-12 complex is associated with FRAP. FRAP is a key regulatory protein that controls cell metabolism, growth and proliferation; a dysfunctional FRAP, thus, explains the cell cycle arrest caused by everolimus. Everolimus has, therefore, a mechanism of action different from cyclosporine. In preclinical models of allotransplantation, the higher efficiency of the combination of everolimus with cyclosporine was shown, compared with the isolated use of each of them.

The effect of everolimus is not limited to the effect on T cells. It inhibits growth factor-stimulated proliferation of both hematopoietic and non-hematopoietic cells (for example, smooth muscle cells). Stimulated growth factor proliferation of vascular smooth muscle cells, which is triggered by damage to the 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 neointima formation in rats with aortic allograft.

Pharmacokinetics

Suction. After ingestion C_max is achieved in 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 dispersible pills compared to pills is 90%.

Food effect: C_max and AUC of everolimus decreased by 60 and 16%, respectively, when taking pills with very fatty foods. To minimize variability, Certican^® should be taken either 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 values in the range from 5 to 5000 ng / ml. In healthy volunteers and patients with moderate hepatic impairment, plasma protein binding is approximately 74%. V_SS in the final phase in patients after kidney transplantation, being 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 main metabolites are formed by the hydrolysis of cyclic lactone. None of them has significant immunosuppressive activity. In the systemic circulation is mainly everolimus.

Derivation. After administration of a single dose of radiolabelled everolimus to patients after transplantation receiving cyclosporine, most of the (80%) radioactivity was detected in the feces, a small amount (5%) was excreted in the urine. Unchanged substance was not detected either in the urine or in the feces.

Pharmacokinetics in balance

Pharmacokinetics in patients with renal and cardiac transplants who received everolimus 2 times per day simultaneously with cyclosporine in the form of a microemulsion was comparable.The equilibrium state was reached on the 4th day with blood cumulation in concentrations that were 2-3 times higher than the blood concentration after the first dose. After taking the drug T_max is 1-2 hours. When taking the drug in doses of 0.75 and 1.5 mg 2 times a day, the average values of C_max make up (11.1 ± 4.6) ng / ml and (20.3 ± 8.0) ng / ml, 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 C₀ everolimus in 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 exposure of everolimus remains stable all the time during the first year after transplantation. WITH₀ highly correlated with AUC, with a correlation coefficient fluctuating 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 V_SS makes 110 l (dispersion - 36%). T_1/2 is (28 ± 7) hours

Pharmacokinetics in special clinical situations

Liver dysfunction. In 8 patients with moderately severe liver dysfunction (class B on the Child-Pough scale), the AUC of everolimus increased approximately 2 times compared with that in 8 healthy volunteers. AUC was positively correlated with serum bilirubin concentration and an increase in PV and negatively correlated with serum albumin concentration. If the concentration of bilirubin was> 34 mcmol / l, PT was> 1.3 INR (prolongation> 4 sec) and / or albumin concentration was <35 g="" l="" then="" there="" was="" a="" tendency="" to="" an="" increase="" in="" auc="" patients="" with="" moderately="" severe="" liver="" failure="" the="" impact="" of="" child-pugh="" class="" c="" on="" has="" not="" been="" studied="" but="" it="" is="" probably="" same="" or="" more="" pronounced="" than="" effects="" moderate="" p="">

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

Pediatrics. The everolimus Cl increased in linear dependence on the patient's age (from 1 to 16 years), the body surface area (0.49–1.92 m²) and body weight (11–77 kg). In equilibrium, Cl was (10.2 ± 3.0) l / h / m², T_1/2 - (30 ± 11) hours

Nineteen de novo patients after kidney transplantation at the age from 1 year to 16 years received the drug Certican^® in the form of pills dispersed 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 corresponded to that of adults receiving 0.75 mg 2 times / day. At equilibrium, 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 (dose adjustment is not required).

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

Impact on effectiveness. For recipients of the kidney and heart within 6 months after transplantation, a relationship was found between the basal concentration of everolimus and the frequency of acute rejection confirmed by biopsy and thrombocytopenia.

Table

Kidney transplantation
WITH₀, 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 (<100 10="" sup="">9/ l)	10%	9%	7%	14%	17%
Heart transplantation
WITH₀, 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 (<75 10="" sup="">9/ l)	5%	5%	6%	8%	9%

Indications

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

Composition

active substance: everolimus 50 mcg

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Dosage and Administration

The certican is taken internally, or always with food, or always without it. The recommended initial dose of Sertikan for adult patients with renal and cardiac transplants is 0.75 mg 2 times / day. The drug should be started as soon as possible after transplantation. The daily dose of Sertikan is always divided into 2 doses. The certificate is taken at the same time with cyclosporine in the form of a microemulsion. Correction of Sertikan's dosing regimen may be required, taking into account plasma concentrations achieved, tolerability, individual response to treatment, changes in concomitant drug therapy and the clinical situation. Correction of the dosing regimen can be performed at intervals of 4-5 days.

Adverse reactions

Listed below are undesirable reactions that may or may be associated with the use of Certican.^®which were registered in phase III clinical studies (kidney or heart transplantation).

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

From the hematopoietic system and lymphatic system: very often - leukopenia¹; often - thrombocytopenia¹anemia¹, coagulopathy, thrombotic thrombocytopenic purpura / hemolytic uremic syndrome; sometimes hemolysis.

On the part of the endocrine system: sometimes - hypogonadism in men (reduced testosterone levels, increased LH levels).

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

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

On the part of 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, abnormal liver function, jaundice, increased levels of ALT, ACT, GGT.

From the skin and subcutaneous tissue: often - angioedema⁴, acne, complications from a 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 who received the drug at a dose of 3 mg / day.

² with heart transplantation.

³ kidney transplantation.

⁴ mainly in patients taking simultaneously 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 Certican^® (1.5 or 3 mg / day) in combination with other immunosuppressants. Malignant neoplasms of the skin were registered in 1.3% of patients, 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, an increase in serum creatinine concentration was observed more frequently in patients receiving Certican.^® in combination with a full dose of cyclosporine in the form of a microemulsion than in control patients. The overall incidence of adverse events was lower with a reduced dose of cyclosporine in the form of a microemulsion.

The safety profile of the drug Certain^® in studies using the drug together with a reduced dose of cyclosporine was the same as in the 3 main studies where the standard dose of cyclosporine was prescribed. However, when using the drug Certain^® along with a reduced dose of cyclosporine, an increase in plasma creatinine was less frequently observed and a lower mean value and median plasma creatinine concentration was observed than in other phase III studies.

When using m-TOR inhibitors, including Certican^®, rarely there was a lesion of the lung parenchyma, such as 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 the purpose of the GCS was noted the disappearance of these undesirable reactions.

Contraindications

Hypersensitivity to everolimus, sirolimus or other components of Sertikan.

Drug interactions

Metabolized with the participation of CYP3A4 isoenzyme, is a substrate for the protein carrier P-glycoprotein, therefore, use with powerful inhibitors or inducers of CYP3A4 is not recommended. P-glycoprotein inhibitors can reduce the release of everolimus from intestinal cells and increase its concentration in serum. Everolimus was a competitive inhibitor of CYP3A4 and CYP2D6, potentially increasing the concentrations of drugs metabolized with the participation of these enzymes. Care should be taken when simultaneously applying everolimus with CYP3A4 and CYP2D6 substrates, which have a narrow therapeutic index. The bioavailability of everolimus is significantly increased with the simultaneous use of cyclosporine (an inhibitor of CYP3A4 / P-glycoprotein). 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 only one everolimus. When changing the dose of cyclosporine, a dose adjustment of everolimus may be required. The clinical significance of the effect of everolimus on the pharmacokinetics of cyclosporine is minimal in patients with kidney and heart transplants receiving cyclosporine in the form of a microemulsion. The use of everolimus after multiple doses of rifampicin (inducer CYP3A4), increases the clearance of everolimus by 3 times, reduces Cmax by 58% and AUC - by 63%. Combined use of riveampin with everolimus is not recommended. Taking a single dose of everolimus with atorvastatin (CYP3A4 substrate) or pravastatin (P-glycoprotein substrate) has no clinical effect on the pharmacokinetics of atorvastatin, pravastatin, everolimus and on 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) can increase the concentration of everolimus in the blood. CYP3A4 inducers (St. John's wort, carbamazepine, phenobarbital, phenytoin, efavirenz, nevirapine) can 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. With everolimus treatment, vaccination may be less effective. The use of live vaccines should be avoided.

Pregnancy and Lactation

Data on the use of the drug Certain^® during pregnancy are absent.

Experimental studies have shown the presence of toxic effects on reproduction, including embryotoxicity and fetotoxicity. It is not known whether there is a potential risk to a person. Do not use the drug Certified^® in pregnant women, except in cases where the expected benefit from therapy outweighs the potential risk to the fetus.

Women of childbearing age should be advised to use effective methods of contraception during the period of 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 rapidly penetrated the milk of lactating rats. Therefore, women receiving the drug Certain^®should not breastfeed.

Special instructions

Therapy with Certican^® Only physicians with experience in immunosuppressive therapy after organ transplantation and who have the ability to monitor the concentration of everolimus in whole blood should begin and conduct it.

In clinical studies, the drug Certain^® used simultaneously with cyclosporin in the form of a microemulsion, basiliximab and GCS. Use of the drug Certain^® in combination with other immunosuppressive agents is not well understood.

The use of the drug in patients with high immunological risk is not well understood.

The combined use of the drug Certican is not recommended.^® with strong CYP3A4 inhibitors (for example ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir) and inducers (for example rifampicin, rifabutin), except for those cases where the expected benefit of such therapy exceeds the potential risk.

It is recommended to control the concentration of everolimus in whole blood with simultaneous use with inducers or inhibitors of CYP3A4 and after their withdrawal.

In patients receiving immunosuppressive therapy, including the drug Certican^®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 rather than with the use of a specific drug. Patients should be monitored regularly to detect skin tumors, recommend minimizing exposure to UV radiation, sunlight and using appropriate sunscreen.

Hyperimmunosuppression, including and when using medication based on the drug Sertikan^® predisposes to the development of infections, especially caused by opportunistic pathogens.

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

In patients with a persistent clinical picture of pneumonia with the ineffectiveness of antibiotic therapy and the exclusion of infectious, neoplastic and other non-drug-related processes, interstitial lung damage 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 the drug Certain^® with cyclosporine 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 the drug Certain^®, should be monitored to identify hyperlipidemia and, if necessary, to carry out treatment with lipid-lowering agents and prescribe an appropriate corrective diet. It is necessary to assess the risk / benefit ratio for patients who have hyperlipidemia before initiating therapy with immunosuppressive drugs, including Certican.^®. You should also evaluate the ratio of the risk / benefit of continuing therapy with Certican.^® in patients with severe refractory hyperlipidemia.

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

Influence on ability to drive motor transport and work with mechanisms. Studies of the effect of the drug Certain^® on the ability to drive and work with the mechanisms were not carried out.

Overdosage

Experimental studies have shown that everolimus has a low potential for acute toxicity. After ingestion of the drug at a dose of 2000 mg / kg, no one-time deaths or severe toxicity were observed in mice and rats (control over a range of values).

Reports of overdose cases in humans are very limited. There is a single fact of accidental ingestion of 1.5 mg of everolimus by a child at the age of 2 years, and no adverse events were observed. With a single oral dose of 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.