Everolimus - instructions for use, doses, side effects, contraindications, price, where to buy - geotar medicinal reference book. Everolimus is a new generation antitumor drug. Pharmacokinetics in certain groups of patients.

Afinitor: instructions for use and reviews

Afinitor is an antitumor drug, a protein tyrosine kinase inhibitor.

Release form and composition

Afinitor is available in the following forms:

dispersible tablets: flat, round, white to white with a yellowish tint, chamfered; on one side there is embossing “D2”, “D3” or “D5” (for tablets of 2 mg, 3 mg or 5 mg, respectively), on the other - NVR (10 pieces in blisters, 3 blisters in a cardboard pack);
tablets: oblong, flat, white to white with a yellowish tint, chamfered; on one side there is embossing LCL, “5” or UHE (for tablets 2.5 mg, 5 mg or 10 mg, respectively), on the other - NVR (2.5 mg tablets - 10 pieces in blisters, 3 blisters in a cardboard box ; tablets 5 mg and 10 mg - 10 pieces in blisters, in a cardboard pack 3, 6 or 9 blisters).

Composition of 1 dispersible tablet:

active ingredient: everolimus – 2 mg, 3 mg or 5 mg;
auxiliary components: mannitol, colloidal silicon dioxide, butylated hydroxytoluene, microcrystalline cellulose, lactose monohydrate, magnesium stearate, hypromellose, crospovidone.

Composition of 1 tablet:

active ingredient: everolimus – 2.5 mg, 5 mg or 10 mg;
auxiliary components: crospovidone, lactose monohydrate, butylated hydroxytoluene, lactose anhydrous, magnesium stearate, hypromellose.

Pharmacological properties

Pharmacodynamics

Everolimus inhibits proliferative signal transduction. This substance selectively inhibits the mammalian target of rapamycin, the serine-threonine protein kinase mTOR, specifically affecting the mTORC1 complex of the signal-transforming mTOR kinase and the regulatory raptor protein. The mTORC1 complex regulates protein synthesis in the distal part of the PI3K7AKT-dependent cascade, the normal function of which is disrupted in the development of most malignant tumors. The active substance of the drug Afinitor has a high-affinity interaction with the intracellular receptor protein FKBP12. Due to the connection between the PKBP12-everolimus and mTORC1 complexes, the signaling function of the latter is inhibited.

The signaling ability of mTORC1 is realized through modulating the phosphorylation of distal effectors: ribosomal protein S6 kinase (S6K1), eukaryotic cell initiation factor and 4E-binding protein (4E-BP1). Due to mTORC1 inhibition, the function of the 4E-BP1 and S6K1 proteins and, accordingly, the translation of the main proteins encoded by mRNA and regulating the cell cycle, glycolysis and cell adaptation to low oxygen levels (hypoxia) are disrupted. As a result, tumor growth and the expression of hypoxia-inducible factors (for example, the transcription factor HIF-1) are suppressed, which reduces the expression of factors (for example, vascular endothelial growth factor) that enhance angiogenesis - the process of formation of new blood vessels in the tumor. Signaling through mTORC1 is regulated by tumor suppressor genes—tuberous sclerosis genes TSC1 and TSC2. In the presence of tuberous sclerosis, which is a genetically determined disease, inactivating mutations in both or one of the TSC1 and TSC2 genes cause the formation of multiple hamartomas with different localizations.

Everolimus is an active inhibitor of the growth and proliferation of fibroblasts, tumor, endothelial and smooth muscle tissues of blood vessels.

In subependymal giant cell astrocytomas associated with tuberous sclerosis, after six months of everolimus therapy, patients showed a statistically significant decrease in tumor volume (in 75% of patients, the tumor volume reduction was at least 30%, in 32% of patients, at least 50%). As a result of taking the drug, patients had no new lesions, no worsening hydrocephalus or signs of increased intracranial pressure, and no need for surgical treatment of subependymal giant cell astrocytomas. The sustained efficacy of everolimus was confirmed during long-term follow-up of patients with subependymal giant cell astrocytomas associated with tuberous sclerosis.

Pharmacokinetics

Absorption

After oral administration of 5–70 mg of the drug (on an empty stomach or with a small amount of low-fat food), the time to reach the maximum concentration (Cmax) in the blood ranges from 1 to 2 hours. C max when taking Afinitor daily varies in proportion to the dose taken in the range of 5–10 mg. In the case of a single dose of everolimus at a dose of 20 mg or higher, the increase in its maximum concentration occurs to a lesser extent, while the values of the area under the pharmacokinetic curve (AUC) when taking 5-70 mg of the drug increase in proportion to the dose.

When everolimus 10 mg was administered orally with a high-fat meal, Cmax and AUC of the drug decreased by 54% and 22%, respectively.

Administration with a low-fat meal resulted in a decrease in Cmax and AUC by 42% and 32%, respectively. In healthy volunteers, when a single dose of 9 mg everolimus (in the form of 3 mg dispersible tablets) was administered with a low-fat or high-fat meal, Cmax decreased by 50.2% and 59.8%, respectively, and AUC decreased, respectively. by 29.5% and 11.7%.

Drug elimination rates within 1 day were not significantly related to food intake.

Relative bioavailability of dispersible tablets

When oral dispersible aqueous tablets and everolimus immediate-release tablets were administered orally, the area under the concentration-time curves were equivalent. The minimum concentration of everolimus achieved 1 day after its administration was comparable for both of these dosage forms. When using dispersible tablets, the Cmax of everolimus was slightly lower (in the range of 64–80% of the values typical for taking immediate-release tablets).

Distribution

In patients with cancer who took everolimus at a dose of 10 mg per day, the concentration of the drug in plasma was about 20% of its concentration in whole blood. The percentage of everolimus in the blood to its content in the blood plasma is dependent on the content of the compound in the range of 5–5000 ng/ml and varies in the range of 17–73%. In both healthy volunteers and patients with moderate liver dysfunction, about 74% of the drug is bound to plasma proteins.

Experimental studies have shown that, as a result of intravenous administration of everolimus, the dose dependence of its penetration through the blood-brain barrier is nonlinear. This fact indicates the supposed saturation of the blood-brain barrier pump, which ensures that the active substance enters the brain tissue. Penetration through the blood-brain barrier is also indicated by data from studies in animals receiving everolimus orally.

Metabolism

Everolimus is a substrate of P-glycoprotein and the CYP3A4 isoenzyme. After oral administration of Afinitor, everolimus circulates in the blood mainly unchanged. There are six known major metabolites of everolimus, including three monohydroxylated metabolites, a phosphatidylcholine conjugate, and two ring-open hydrolytic products. The activity of these metabolites is approximately 100 times lower than that of everolimus. It is generally accepted that the main overall pharmacological activity of everolimus is due to the action of the unchanged compound.

Removal

After a single dose of radiolabeled everolimus, 80% of the radioactivity is detected in the feces, and 5% is excreted by the kidneys. Everolimus in unchanged form was not detected in feces and urine.

Pharmacokinetics at steady state

When administered daily or weekly, the 0-τ AUC values of everolimus are proportional to the dose taken in the range of 5–10 mg per day or 5–70 mg of Afinitor per week. When taken daily, a steady state is achieved within 2 weeks. When everolimus is used at a dose of 5–10 mg per day or per week, Cmax is proportional to the dose. When taking everolimus at a dose of 20 mg per week or higher, C max increases to a lesser extent. The time to reach Cmax in blood plasma ranges from 1 to 2 hours. In the case of daily administration of everolimus after reaching a steady state, there is a significant correlation between the AUC 0-τ value and the content of everolimus in the blood before the next dose of the drug. The half-life is approximately 1.25 days.

Pharmacokinetics in selected patient groups

In case of liver dysfunction, the increase in systemic exposure of Afinitor is:

in patients with mild liver dysfunction (class A according to the Child-Pugh classification) - 1.6 times;
in patients with moderate liver dysfunction (class B according to the Child-Pugh classification) – 3.3 times;
in patients with severe liver dysfunction (class C according to the Child-Pugh classification) - 3.6 times.

In case of liver dysfunction, everolimus dose adjustment is required.

In case of post-transplant renal dysfunction (creatinine clearance 11–107 ml/min) in patients after organ transplantation, the pharmacokinetics of everolimus did not change. In progressive solid tumors, a significant dependence of everolimus clearance (CL/F) on creatinine clearance (creatinine clearance 25–178 ml/min) was not detected.

In patients under 18 years of age with subependymal giant cell astrocytomas (SEGA), the individual steady-state minimum therapeutic concentration of everolimus (C min) was directly proportional to the daily dose and ranged from 1.35 to 14.4 mg/m2. In patients with SEGA who have not reached the age of 18 years, the geometric mean C min value, normalized to the dose taken (in mg/m2), is significantly lower compared to adult patients, which may indicate increased clearance of everolimus in children.

In patients aged 27–85 years after oral administration of Afinitor, no significant effect of age on everolimus clearance (with CL/F from 4.8 to 54.7 l/h) was detected.

Impact of race

After oral administration of the drug, the clearance of everolimus (CL/F) did not differ between Mongoloid and Caucasian individuals with similar liver function.

Based on the results of a population pharmacokinetic analysis, after organ transplantation in representatives of the Black race, the clearance of everolimus (CL/F) (when administered orally) was on average 20% greater than in individuals of the Caucasian race.

Effect of Exposure on Efficiency

With daily administration of everolimus at a dose of 5 to 10 mg, a certain correlation was recorded between a decrease in 4E-BP1 phosphorylation in tumor tissues and C min in the blood at steady state.

There is additional evidence that the decrease in phosphorylation of S6 kinase is very sensitive to the inhibition of the serine-threonine protein kinase mTOR by everolimus. A complete suppression of phosphorylation of the translation initiation factor eIF-4G was recorded across the entire range of everolimus C min values in the blood when taking Afinitor at a dose of 10 mg daily.

In patients with subependymal giant cell astrocytomas, when C min is doubled, the tumor size decreases by 13%, while a decrease in tumor size of 5% is considered statistically significant.

Indications for use

subependymal giant cell astrocytomas (SEGA) associated with tuberous sclerosis (TS) in persons over three years of age (if surgical resection of the tumor is not possible);
metastatic and/or widespread neuroendocrine tumors of the lung, gastrointestinal tract and pancreas;
angiomyolipoma of the kidney associated with tuberous sclerosis (if immediate surgical intervention is not required);
metastatic and/or advanced renal cell carcinoma (if antiangiogenic treatment is ineffective);
hormone-dependent advanced breast cancer in women after menopause after previous endocrine treatment (in combination with an aromatase inhibitor).

According to the instructions, Afinitor in the form of dispersible tablets is used only for the treatment of patients with SEGA associated with TS.

Contraindications

Absolute:

liver dysfunction (Child-Pugh class A, B and C) in children and adolescents 3–18 years old with SEGA;
liver dysfunction (Child-Pugh class C) in adult patients with SEGA;
children up to 3 years of age (with SEGA), up to 18 years (other indications);
period of pregnancy and lactation;
simultaneous use with strong inducers of P-glycoprotein or inducers of the CYP3A4 isoenzyme;
hypersensitivity to any of the components of the drug or other rapamycin derivatives.

Relative (Afinitor is used with caution):

rare hereditary disorders associated with galactose intolerance, glucose-galactose malabsorption or severe lactase deficiency;
surgical interventions (as the drug can slow down the wound healing process);
simultaneous use with moderate P-glycoprotein inhibitors or CYP3A4 inhibitors.

Instructions for use of Afinitor: method and dosage

Afinitor is taken orally once a day at the same time (preferably in the morning). Tablets are taken on an empty stomach or after a light snack that does not contain fat.

Afinitor dispersible tablets are intended for suspension and should not be chewed, crushed or swallowed whole. The suspension is prepared in a small glass or in a special syringe for suspensions, using water for dilution, and taken immediately after preparation.

Afinitor tablets are swallowed whole with a glass of water. If the patient, for health reasons, cannot swallow the tablet whole, it is recommended to dissolve it in 30 ml of water immediately before use, drink the resulting solution, then rinse the glass again with 30 ml of water and drink the solution (this ensures that the full dose is taken).

Treatment is continued as long as the clinical effect of Afinitor is maintained and there are no signs of intolerable toxicity.

For the treatment of patients with SEGA, the starting dose of Afinitor is 4.5 mg/m2 body surface, rounded to the nearest available drug dosage. To obtain the desired dose, you can combine tablets of different dosages.

Approximately 2 weeks after initiation of SEGA treatment or after any change in liver function, everolimus blood concentrations should be assessed. Dosage titration may be necessary to achieve optimal therapeutic effect, as well-tolerated and effective doses vary for each patient.

SEGA tumor volume should be assessed every three months after initiation of therapy.

When prescribing Afinitor for other indications (except SEGA), the recommended dose is 10 mg per day once.

If severe and/or intractable side effects develop, the dose of Afinitor should be reduced by 50% or treatment should be temporarily discontinued. Patients receiving everolimus at a dose of 2.5 mg per day can be switched to taking the drug every other day.

When co-administered with moderate P-glycoprotein inhibitors or CYP3A4 inhibitors, reduce the dose of Afinitor to 5 mg per day. If severe and/or difficult to tolerate side effects develop, the drug is taken 5 mg per day every other day.

When co-administered with strong inducers of P-glycoprotein or inducers of the CYP3A4 isoenzyme, the dose of everolimus can be gradually increased from 10 to 20 mg per day (dose increments are 5 mg).

In case of impaired renal function and in patients 65 years of age and older, no dose adjustment is required.

In case of liver dysfunction, the dose is adjusted as follows:

SEGA in patients over 18 years of age with mild liver dysfunction - 75% of the standard dose calculated by body surface area;
SEGA in patients over 18 years of age with moderate liver dysfunction - 25% of the standard dose calculated by body surface area;
SEGA in patients over 18 years of age with severe liver dysfunction - Afinitor is contraindicated;
other indications (except SEGA) for mild liver dysfunction – 7.5 mg per day;
other indications (except SEGA) for moderate liver dysfunction - 2.5 mg per day;
other indications (except SEGA) for severe liver dysfunction - Afinitor is contraindicated.

Side effects

digestive system: very often - stomatitis, changes in taste, anorexia, vomiting, nausea, diarrhea; often – dyspepsia, dysphagia, abdominal pain, dry mouth;
cardiovascular system: often - increased blood pressure; sometimes – congestive heart failure;
nervous system and sensory organs: very often – headache; often - sleep disturbances (insomnia), swelling of the eyelids, conjunctivitis; sometimes – loss of taste;
respiratory system: very often - pneumonitis, shortness of breath, cough, nosebleeds; often – hemoptysis;
hematopoietic system: very often - anemia, neutropenia, lymphocytopenia, thrombocytopenia;
endocrine system: often - exacerbation of diabetes mellitus; sometimes – diabetes mellitus, diagnosed for the first time;
urinary system: often - increased urination during the daytime;
skin and subcutaneous tissue: very often - dry skin, itching and rash; often – erythema, hand-foot syndrome;
metabolism: very often - increased concentrations of glucose, cholesterol, creatinine, triglycerides, decreased concentrations of phosphorus in the blood, increased activity of liver enzymes; often - increased bilirubin levels in the blood;
general reactions: very often - asthenia, secondary infections, increased fatigue, peripheral edema; often – chest pain, dehydration; sometimes – decrease in body weight, increase in temperature, slow healing of wounds.

During treatment with Afinitor, isolated cases of the following adverse reactions were also observed: bleeding of various localizations of the first degree of severity, hypersensitivity manifested by flushing of the face, shortness of breath, chest pain, angioedema or anaphylactic reactions.

In clinical studies, cases of exacerbation of viral hepatitis B (including deaths) and the development of hyperglycemia were noted.

Overdose

No cases of drug overdose have been recorded. With a single oral dose of Afinitor at a dose of up to 70 mg, tolerability was satisfactory.

In case of overdose of Afinitor, the patient should be monitored and appropriate symptomatic therapy provided.

special instructions

Treatment with Afinitor is carried out under the supervision of a specialist with experience in working with antitumor drugs.

During treatment and for at least two months after discontinuation of everolimus, it is recommended to use reliable methods of contraception.

Before starting therapy and periodically during the use of Afinitor, renal function, glucose levels and drug concentrations in the blood should be monitored, a clinical blood test should be performed, the content of blood cells and the concentration of triglycerides and cholesterol should be monitored.

If symptoms of non-infectious pneumonitis appear, it may be necessary to reduce the dose of everolimus or completely discontinue Afinitor.

During treatment with Afinitor, the risk of developing viral, bacterial, protozoal and fungal infections increases, therefore, if signs of any disease appear, you should inform your doctor, who will prescribe appropriate treatment.

For invasive systemic fungal infection, Afinitor should be discontinued and appropriate antifungal therapy should be administered.

For stomatitis, inflammation and ulcerations of the oral mucosa, local treatment is recommended, but hydrogen peroxide, thyme derivatives, iodine and products containing alcohol should not be used to rinse the mouth, as their use may worsen the patient's condition.

When prescribing Afinitor, children and adolescents under 18 years of age should first be vaccinated with antiviral vaccines according to the local vaccination schedule.

During treatment, care must be taken when driving a car and engaging in other potentially dangerous activities (work of a dispatcher, operator, etc.).

Use during pregnancy and lactation

Afinitor is contraindicated for use during pregnancy and breastfeeding. During therapy with Afinitor and for at least 2 months after its completion, the use of reliable methods of contraception is recommended.

Use in childhood

Afinitor is not recommended for use in patients under 1 year of age. When treating children with subependymal giant cell astrocytomas, doses similar to those in adult patients are recommended (excluding cases of impaired liver function).

In case of impaired liver function of classes A, B, C according to the Child-Pugh classification, Afinitor is contraindicated for use in patients under the age of 18 years for the treatment of subependymal giant cell astrocytomas associated with tuberous sclerosis.

For impaired renal function

In case of impaired renal function, no dose adjustment is required.

For liver dysfunction

The drug is contraindicated for the treatment of patients with subependymal giant cell astrocytomas with severe liver dysfunction (class C according to the Child–Pugh classification). In severe liver failure, the drug is not recommended for use (except in cases where the potential risk is lower than the expected benefit).

For mild to moderate liver dysfunction (classes A and B according to the Child-Pugh classification), dose adjustment is required.

In case of liver dysfunction of classes A, B, C according to the Child-Pugh classification, it is prohibited to use Afinitor in the treatment of subependymal giant cell astrocytomas associated with tuberous sclerosis in patients under the age of 18 years.

Use in old age

When treating elderly patients, no dose adjustment is required.

Drug interactions

P-glycoprotein inhibitors may increase serum concentrations of everolimus. Afinitor may increase plasma concentrations of drugs metabolized by inhibitors of CYP3A4 and CYP2D6.

The bioavailability of everolimus increases when administered concomitantly with erythromycin, verapamil and cyclosporine.

The concentration of everolimus in the blood may increase when used simultaneously with the following drugs: macrolide antibiotics (erythromycin, etc.), antifungals (fluconazole), protease inhibitors (indinavir, nelfinavir, amprenavir), calcium channel blockers (diltiazem, nicardipine, verapamil).

The concentration of everolimus in the blood may decrease when used simultaneously with the following drugs: rifampicin, anticonvulsants (phenobarbital, carbamazepine, phenytoin), St. John's wort, drugs for the treatment of HIV (nevirapine, efavirenz).

When used together with glucocorticosteroids or other immunosuppressive drugs, the likelihood of developing Pneumocystis pneumonia increases; with ACE inhibitors – the risk of developing angioedema increases.

Immunosuppressants may affect the response to vaccination, so vaccination may be less effective during treatment with everolimus. It is recommended to avoid the use of live vaccines.

Analogues

Analogs of Afinitor are: Gleevec, Votrien, Certican, Nexavar, Everolimus.

Terms and conditions of storage

Store in a dry, dark place at a temperature not exceeding 30 °C. Keep away from children.

Shelf life – 3 years.

Structural formula

Russian name

The Latin name of the substance is Everolimus

Everolimusum ( genus. Everolimusi)

Chemical name

Dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]propan-2-yl]-19,30-dimethoxy-15,17,21 ,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclohexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone

Gross formula

C 53 H 83 NO 14

Pharmacological group of the substance Everolimus

CAS code

159351-69-6

Use during pregnancy and breastfeeding

Typical clinical and pharmacological article 1

Pharmaceutical action. Immunosuppressive agent, proliferative signal inhibitor. It has an immunosuppressive effect by inhibiting antigen-activated T-cell proliferation, clonal expansion caused by T-cell interleukins (interleukin-2, interleukin-15). Inhibits the intracellular signaling pathway, which normally leads to cell proliferation triggered by the binding of T-cell growth factors to the corresponding receptors. Blockade of the signal leads to a stop in cell division at stage G 1 of the cell cycle. At the molecular level, it forms a complex with the cytoplasmic protein FKBP-12. Phosphorylation of p70 S6 kinase stimulated by growth factor is inhibited. Phosphorylation of p70 S6 kinase is under the control of FRAP, i.e. the everolimus-FCBP-12 complex binds to FRAP. FRAP is a key regulatory protein that controls cellular metabolism, growth and proliferation; disruption of its functions explains the cell cycle arrest caused by everolimus. Everolimus has a different mechanism of action from cyclosporine. The combination of everolimus with cyclosporine is more effective than when each of them is used alone. Everolimus inhibits the proliferation of hematopoietic and non-hematopoietic cells (smooth muscle cells). The proliferation of vascular smooth muscle cells, triggered by damage to endothelial cells, leads to the formation of neointima, which plays a key role in the pathogenesis of chronic rejection.

Pharmacokinetics. The bioavailability of dispersible tablets (compared to a regular tablet) is 0.9. TC max - 1-2 hours. TC ss - on the 4th day. When used in doses of 0.75 mg and 1.5 mg 2 times a day, Cmax is 6.5-15.7 and 12.3-28.3 ng/ml, respectively; AUC - 44-106 and 72-160 ng x h/ml, respectively. When used in doses of 0.5 mg and 1.5 mg 2 times a day, the basal concentration in the blood (determined in the morning before taking the next dose) is 2.0-6.2 and 2.5-11.7 ng/ml, respectively. Basal concentration correlated with AUC (correlation coefficient 0.86-0.94). The concentration in the blood is proportional to the dose taken (in the dose range of 0.5-15 mg). The ratio of concentration in blood and concentration in plasma is 17-73% (depending on concentration values in the range of 5-5000 ng/ml). When taking the tablets with a very fatty meal, Cmax and AUC are reduced by 60% and 16%, respectively. Protein binding - 74%. Distribution volume - 235-449 l; volume of distribution (at steady state) - 110 l (deviation 36%). Everolimus is a substrate of CYP3A4 and P-glycoprotein. The main metabolic pathways are monohydroxylation and O-dealkylation. The two main metabolites are formed by hydrolysis of the cyclic lactone and do not have significant immunosuppressive activity. General clearance - 8, l/h (deviation - 27%). T1/2 - 21-35 hours. Excreted by the intestines (80%) and kidneys (5%). In patients with liver failure (class B on the Child-Pug scale), AUC increases by 2 times. AUC correlates positively with bilirubin concentrations and increased prothrombin time and negatively with serum albumin concentrations. In children from 1 year to 16 years, clearance increases linearly depending on age, body surface area (0.49-1.92 sq.m.), body weight (11-77 kg); in equilibrium, the clearance is 7.2-12.2 l/h/sq.m; T1/2 - 19-41 hours. In children 1-16 years old receiving everolimus in the form of dispersible tablets at a dose of 0.8 mg/m (maximum 1.5 mg) 2 times a day with cyclosporine (microemulsion), AUC - 60-114 ng x h/ml, which corresponds to that in adults receiving the drug at a dose of 0.75 mg 2 times a day. The basal concentration at steady state is 2.7-6.1 ng/ml. In patients aged 16-70 years, a decrease in clearance of 0.3% per year was observed. The total clearance in patients of the Negroid race is 20% higher. The basal concentration of everolimus, the incidence of acute rejection and thrombocytopenia are associated with each other (in kidney and heart transplant recipients within 6 months after transplantation). Everolimus exposure remains stable throughout the first year after transplantation. The pharmacokinetics in patients with kidney and heart transplants receiving everolimus 2 times a day simultaneously with cyclosporine (in the form of a microemulsion) are comparable.

Indications. Prevention of graft rejection in adult kidney and heart transplant recipients with low and moderate immunological risk receiving basic immunosuppressive therapy with cyclosporine (in the form of a microemulsion) and corticosteroids.

Contraindications. Hypersensitivity, childhood.

Carefully. Liver failure, chronic renal failure, pregnancy. For dosage forms containing lactose (additionally): hereditary galactose intolerance, lactase deficiency, glucose-galactose malabsorption.

Dosing. Orally, with or without food only (for minimal variability), immediately after transplantation, simultaneously with cyclosporine (microemulsion); The tablets are swallowed whole with a glass of water (or in the form of dispersible tablets) 0.5 mg 2 times a day. After 4-5 days, the dosage regimen is adjusted (based on the basal concentration of everolimus).

In case of liver failure (class A or B on the Child-Pug scale), the dose is reduced by 2 times (compared to the average dose) in cases where there is a combination of two of the indicators: bilirubin more than 34 µmol/l, albumin less than 35 g/l, prothrombin time is more than 1.3 according to INR (increase of more than 4 s). The dose is titrated based on therapeutic monitoring.

Blacks (based on limited information) may require a higher dose to achieve the same effect as other patients receiving the drug at recommended adult doses.

Side effect. Frequency: very common (more than 1/10), common (more than 1/100 and less than 1/10), uncommon (more than 1/1000 and less than 1/100), rare (more than 1/10,000 and less than 1/1000) , very rare (less than 1/10000).

From the hematopoietic organs: very often - leukopenia (dose-dependent, more often at a dose of 3 mg/day); often - thrombocytopenia (dose-dependent, more often at a dose of 3 mg/day), anemia (dose-dependent, more often at a dose of 3 mg/day), coagulopathy, thrombotic thrombocytopenic purpura/hemolytic uremic syndrome; infrequently - hemolysis.

From the side of metabolism: very often - hypercholesterolemia, hyperlipidemia; often - hypertriglyceridemia.

From the cardiovascular system: often - increased blood pressure, lymphocele (during kidney transplantation), phlebothrombosis.

From the respiratory system: often - pneumonia; infrequently - pneumonitis.

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

From the skin: often - angioedema (with simultaneous use of ACE inhibitors), acne, complications from the surgical wound; infrequently - rash.

From the musculoskeletal system: infrequently - myalgia.

From the genitourinary system: often - urinary tract infections; uncommon - renal tubular necrosis, pyelonephritis, hypogonadism in men (decreased testosterone concentration, increased LH concentration).

Other: often - viral, bacterial, fungal infections, sepsis, swelling, pain; uncommon - wound infection, hepatitis, liver dysfunction, jaundice, increased ALT, AST, GGT.

It is possible (in patients observed for at least 1 year) the occurrence of lymphomas or lymphoproliferative diseases (in 1.4% of patients receiving everolimus 1.5 mg or 3 mg/day, in combination with other immunosuppressants); malignant skin tumors (in 1.3% of patients), other types of malignancy (in 1.2% of patients).

Overdose. Treatment: symptomatic.

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 with the participation of these enzymes. Caution should be exercised when administering everolimus concomitantly with CYP3A4 substrates and CYP2D6, having 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 and 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.

Special instructions. Treatment should only be performed by physicians experienced in immunosuppressive therapy after organ transplantation and the ability to monitor everolimus whole blood concentrations.

Patients with basal concentrations of 3 ng/mL or more have a lower incidence of acute rejection (renal and cardiac) than patients with basal concentrations less than 3 ng/mL.

In patients with liver failure, while using strong inducers and inhibitors of CYP3A4, when switching to another drug and/or if the dose of cyclosporine is significantly reduced, it is necessary to monitor the concentration of everolimus in the blood.

Everolimus concentrations with dispersible tablets are slightly lower than with conventional tablets.

Since cyclosporine interacts with everolimus, a decrease in the concentration of the latter is possible if the concentration of cyclosporine is significantly reduced (basal concentration less than 50 ng/ml).

Everolimus should not be used long-term with full dose cyclosporine. A reduction in the dose of cyclosporine begins 1 month after renal transplantation, which leads to an improvement in renal function.

Recommended concentration of cyclosporine (2 hours after administration): 0-4 weeks - 1000-1400 ng/ml; 5-8 weeks - 700-900 ng/ml; 9-12 weeks - 550-650 ng/ml; 13-52 weeks - 350-450 ng/ml. In this case, the basal concentration of cyclosporine should be (ng/ml): 1st month - 125-353; 3rd month - 46-216; 6th month - 22-142; 12th month - 33-89.

It is very important (in the early period after transplantation) that everolimus and cyclosporine concentrations are not reduced below the therapeutic range in order to minimize the risk of failure. Before reducing the dose of cyclosporine, it should be clarified that the steady-state concentration of everolimus is 3 ng/ml or more.

There are limited data on the use of everolimus when basal cyclosporine concentrations are less than 50 ng/mL or maintenance cyclosporine concentrations are less than 350 ng/mL.

If the patient does not tolerate a dose reduction of cyclosporine, subsequent use of everolimus should be reconsidered.

In patients after heart transplantation, the dose of cyclosporine should be reduced in the maintenance phase to improve renal function.

If renal function deteriorates or if CC is less than 60 ml/min, adjustment of the therapy regimen is necessary. The dose of cyclosporine is determined based on its basal concentration.

In cardiac transplantation, there are limited data on the use of everolimus when basal cyclosporine concentrations are less than 175 ng/mL in the first 3 months; less than 135 ng/ml - in the 6th month; less than 100 ng/ml - after 6 months.

Everolimus is used simultaneously with cyclosporine in the form of a microemulsion, basiliximab and GCS.

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

Everolimus blood concentrations should be monitored when used concomitantly with CYP3A4 inducers or inhibitors and after their discontinuation.

During treatment, patients should be monitored to identify skin neoplasms; It is necessary to minimize exposure to UV radiation, sunlight, and use appropriate sunscreens. The risk of skin neoplasms is related to the duration and intensity of immunosuppression rather than to the use of a specific drug. Excessive immunosuppression predisposes to the development of infections, especially opportunistic ones. There are reports of fatal infections and sepsis.

Concomitant use of everolimus with cyclosporine (microemulsion) increases serum cholesterol and TG levels, which may require appropriate treatment. Patients should be monitored to identify hyperlipidemia, if necessary, treated with lipid-lowering drugs and prescribed an appropriate diet.

If hyperlipidemia is detected when immunosuppressive drugs are prescribed, it is necessary to assess the risk/benefit ratio.

The risk/benefit ratio of continuing everolimus therapy in patients with severe refractory hyperlipidemia should 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.

Caution should be exercised when simultaneous use of other drugs that have a negative effect on renal function. There are limited data on the use of everolimus in pediatric renal transplant recipients.

In patients with hepatic impairment, basal whole blood concentrations of everolimus should be carefully monitored.

State register of medicines. Official publication: in 2 volumes - M.: Medical Council, 2009. - Volume 2, part 1 - 568 pp.; Part 2 - 560 s.

Certican.

Composition and release form

Everolimus. Dispersible tablets, round, flat (100 mcg, 250 mcg); tablets are round, flat (250 mcg, 500 mcg, 750 mcg, 1 mg).

pharmachologic effect

Immunosuppressive drug. The active substance of the drug, everolimus, is an inhibitor of the proliferative signal. Everolimus exerts its immunosuppressive effect by inhibiting antigen-activated T cell proliferation and, consequently, clonal expansion caused by specific T cell interleukins, such as interleukin-2 and interleukin-15.

Everolimus inhibits the intracellular signaling pathway that normally leads to cell proliferation triggered by the binding of these T cell growth factors to 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-PKBP-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. In preclinical allotransplantation models, the combination of everolimus and cyclosporine has been shown to be more effective than 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.

Pharmacokinetics

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 mg to 15 mg. The bioavailability of dispersible tablets compared to tablets is 0.90 (90% CI 0.76-1.07).

When taking the drug with a very fatty meal, the Cmax AUC of everolimus decreased by 60% and 16%, respectively. To minimize variability, everolimus should be taken either with or without food. Plasma protein binding - 74%. Vd - 342±107 l. T1/2 is 28±7 hours.

Everolimus is a substrate of CYP3A4 and P-glycoprotein. Metabolites do not have significant immunosuppressive activity. Everolimus is found mainly in the systemic circulation. 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, Cmax is 1-2 hours. It is excreted in feces (80%) and urine (5%) in the form of metabolites. Everolimus exposure remains stable throughout the first year after transplantation.

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.

Application

The daily dose of the drug is always divided into 2 doses; the drug is taken either always with food, or always without it, at the same time with cyclosporine in the form of a microemulsion. Adjustment of the dosage regimen may be necessary taking into account achieved plasma concentrations, tolerability, individual response to treatment, changes in concomitant drug therapy and the clinical situation. Correction of the dosage regimen can be carried out at intervals of 4-5 days.

The incidence of biopsy-proven acute rejection was higher in blacks compared to others.

Based on the limited information available, blacks may require a higher dose of the drug to achieve the same effect as other patients receiving the drug at recommended adult doses. Currently available efficacy and safety data are insufficient to make specific recommendations for the use of everolimus in blacks.

In patients with impaired renal function, no dose adjustment is required. In patients with hepatic impairment, basal whole blood concentrations of everolimus should be carefully monitored. In patients with mild to moderate hepatic impairment (Child-Pugh class A or B), the dose should be reduced by approximately 2 times the average dose in cases where there is a combination of two of the following: bilirubin more than 34 µmol/l (more than 2 mg/dl), albumin less than 35 g/l (less than 3.5 g/dl), prothrombin time more than 1.3 MHO (prolongation more than 4 seconds). Further dose titration is carried out based on therapeutic monitoring data. Everolimus has not been studied in patients with severe hepatic impairment (Child-Pugh class C).

Side effect

From the KS side: very often - leukopenia, thrombocytopenia, anemia, coagulopathy, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome; sometimes - hemolysis.
From the side of ES: hypogonadism in men (decreased testosterone levels, increased LH levels).
From the side of metabolism: HCS, hyperlipidemia, hypertriglyceridemia.
On the cardiovascular system: pericardial effusion, increased blood pressure, lymphocele, venous thrombosis.
From the DS side: pleural effusion, pneumonia; sometimes - pneumonitis.
On PS: abdominal pain, diarrhea, nausea, vomiting, hepatitis, liver dysfunction, jaundice, increased ALT, AST, GGT.
From the skin and subcutaneous tissue: angioedema, acne, complications from the surgical wound; sometimes - a rash.
From the side of the respiratory system: myalgia.
For MS: urinary tract infections; sometimes - necrosis of the renal tubules, pyelonephritis.
Other: swelling, pain, viral, bacterial and fungal infections, sepsis; sometimes - wound infection.

Contraindications

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

Pregnancy and lactation

The drug should not be used during pregnancy, unless the expected benefit of therapy outweighs the potential risk to the fetus. While taking the drug, you should stop breastfeeding.

Interaction with other drugs

Everolimus is metabolized mainly in the liver and to some extent in the intestinal wall with the participation of the CYP3A4 isoenzyme. Everolimus is also a substrate for the P-glycoprotein transporter protein. Therefore, the absorption and subsequent elimination of systemically absorbed everolimus may be affected by drugs that interact with CYP3A4 and/or P-glycoprotein.

The combined use of the drug with strong inhibitors or inducers of CYP3A4 is not recommended. P-glycoprotein inhibitors may reduce the release of ererolimus from intestinal cells and increase everolimus serum concentrations. In vitro, everolimus was a competitive inhibitor of CYP3A4 and CVP2D6, potentially increasing plasma concentrations of drugs eliminated by these enzymes. Therefore, caution should be exercised when simultaneous use of the drug with CYP3A4 and CYP2D6 substrates, which have a narrow therapeutic index.

All in vivo interaction studies were conducted without concomitant use of cyclosporine.
The bioavailability of everolimus was significantly increased by concomitant use of cyclosporine (CYPZA4/P-glycoprotein inhibitor). If the dose of cyclosporine is changed, adjustment of the everolimus dosage regimen may be necessary.

Inducers of CYP3A4 may increase the metabolism of everolimus and reduce its concentration 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 while taking the drug. Immunosuppressants may influence vaccination response; During treatment with the drug, vaccination may be less effective. The use of live vaccines should be avoided.

Immunosuppressant, inhibitor of proliferative signal transmission. The immunosuppressive effect is due to the inhibition of 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 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 stage G 1 of the cell cycle.

In addition to its effect on T cells, everolimus 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.

Everolimus is an active inhibitor of the growth and proliferation of tumor cells, endothelial cells, fibroblasts and smooth muscle cells of blood vessels.

In patients with advanced and/or metastatic renal cell carcinoma progressing after prior therapy with tyrosine kinase inhibitors and/or cytokines, everolimus significantly reduced the risk of disease progression and death by 67%. When using everolimus, survival of patients without disease progression was 4.9 months. Within 6 months, 36% of patients receiving everolimus did not experience disease progression. It is believed that the use of everolimus can significantly improve the quality of life of patients (the impact of disease symptoms on various areas of the patient’s life was assessed).

Pharmacokinetics

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 mg to 15 mg.

The ratio of everolimus blood concentration to 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%. V d in the final phase in patients after kidney transplantation who are on maintenance therapy is 342 ± 107 l.

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.

Following administration of a single dose of radiolabeled everolimus to transplant patients receiving cyclosporine, most (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.

In patients with moderately severe liver dysfunction (Child-Pugh class B), the AUC of everolimus increased. AUC was positively correlated with serum bilirubin concentration and prothrombin time increase and negatively correlated with serum albumin concentration. If the bilirubin concentration was > 34 µmol/L, the prothrombin time was > 1.3 INR (prolongation > 4 sec) and/or the albumin concentration was< 35 г/л, то наблюдалась тенденция к увеличению показателя AUC у пациентов с умеренно выраженной печеночной недостаточностью. При тяжелой печеночной недостаточности (класс С по шкале Чайлд-Пью) изменения AUC не изучены, но, вероятно, они такие же или более выраженные, чем при умеренной печеночной недостаточности.

Everolimus clearance increased linearly with patient age (from 1 to 16 years), body surface area (0.49-1.92 m2) and body weight (11-77 kg). At steady state, clearance was 10.2±3.0 l/h/m2, T1/2 - 30±11 hours.

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.

Indications for use

Prevention of kidney and heart transplant rejection in adult recipients with low and average immunological risk receiving basic immunosuppressive therapy (cyclosporine and corticosteroids).

Advanced and/or metastatic renal cell carcinoma (if antiangiogenic therapy is ineffective).

Dosage regimen

Taken orally.

As a means of preventing transplant rejection, the recommended starting dose for adults with kidney and heart transplants is 750 mcg 2 times a day. Application should be started as soon as possible after transplantation. Taken at the same time with cyclosporine in a special dosage form. The dosage regimen of everolimus may need to be adjusted based on achieved plasma concentrations, tolerability, individual response to treatment, changes in concomitant drug therapy and the clinical situation. Correction of the dosage regimen can be carried out at intervals of 4-5 days.

As an antitumor agent, it is used in a dose of 10 mg 1 time/day daily. Treatment is continued as long as the clinical effect remains. If severe and/or intractable adverse reactions develop, the dose should be reduced to 5 mg/day and/or therapy should be temporarily discontinued. When used concomitantly with moderate CYP3A4 inhibitors and P-glycoprotein inhibitors, the dose of everolimus should be reduced to 5 mg/day. If severe and/or intractable adverse reactions develop in patients receiving the drug concomitantly with moderate CYP3A4 inhibitors and P-glycoprotein inhibitors, the dose of everolimus should be reduced to 5 mg/day every other day. When everolimus is used concomitantly with strong CYP3A4 inducers or P-glycoprotein inducers, the dose can be increased gradually from 10 mg/day to 20 mg/day (stepwise dose increase is 5 mg). When discontinuing therapy with strong CYP3A4 inducers or P-gp inducers, everolimus should be used at the dose that was used before starting treatment with the CYP3A4 inducers or P-gp inducers.

In patients with moderate hepatic impairment (Child-Pugh class B), the dose should be reduced to 5 mg/day.

Side effect

From the hematopoietic and lymphatic systems: very often - leukopenia; often - thrombocytopenia, anemia, coagulopathy, thrombotic thrombocytopenic purpura/hemolytic uremic syndrome; sometimes - hemolysis.

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

From the side of metabolism: very often - hypercholesterolemia, hyperlipidemia; often - hypertriglyceridemia.

From the cardiovascular system: often - increased blood pressure, lymphocele, venous thrombosis.

From the respiratory system: often - pneumonia; sometimes - pneumonitis.

From the digestive system: often - abdominal pain, diarrhea, nausea, vomiting; sometimes - hepatitis, liver dysfunction, jaundice, increased ALT, AST, 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.

Others: often - swelling, pain, viral, bacterial and fungal infections, sepsis; sometimes - wound infection.

In controlled clinical studies in which patients were followed for at least one year, the occurrence of lymphomas or lymphoproliferative disease was reported in 1.4% of cases when everolimus was used with other immunosuppressants; malignant neoplasms of the skin (1.3%); other types of malignancy (1.2%).

Use during pregnancy and breastfeeding

There are no data on use during pregnancy. Everolimus should not be used during pregnancy unless the expected benefit to the mother outweighs the potential risk to the fetus.

It is not known whether everolimus is excreted into breast milk in humans. If it is necessary to use everolimus during lactation, the issue of stopping breastfeeding should be decided.

IN experimental studies the presence of toxic effects on reproduction, including embryotoxicity and fetotoxicity, has been shown. It is unknown whether there is a potential risk to humans. It was shown that everolimus and/or its metabolites rapidly penetrated into the milk of lactating rats.

Use for liver dysfunction

U patients with liver dysfunction moderate degree (class B according to the Child-Pugh classification) the dose should be reduced to 5 mg/day. Everolimus has not been studied in patients with severe hepatic impairment. It is recommended to carefully monitor everolimus plasma concentrations in patients with impaired liver function.

Use for renal impairment

special instructions

During treatment, regular monitoring of renal function is recommended. If serum creatinine levels increase, the issue of adjusting the immunosuppressive therapy regimen, in particular reducing the dose of cyclosporine, should be considered. Caution should be exercised when concomitantly using other drugs that may impair renal function.

Concomitant use 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.

Everolimus has not been studied in patients with severe hepatic impairment. It is recommended to carefully monitor everolimus plasma concentrations in patients with impaired liver function.

During treatment, patients should be monitored to identify skin neoplasms. Patients should be regularly monitored for skin lesions, recommended to minimize exposure to ultraviolet radiation, sunlight, and use of appropriate sunscreens.

Use with caution in patients with hyperlipidemia. During treatment, blood levels of cholesterol and triglycerides should be monitored. The risk/benefit ratio of continuing everolimus therapy in patients with severe refractory hyperlipidemia should be assessed. Patients receiving HMG-CoA reductase inhibitors and/or fibrates should be monitored for the development of adverse reactions caused by the use of these drugs.

Excessive immunosuppression predisposes to the development of infections (including opportunistic ones). There are reports of fatal infections and sepsis.

Patients receiving HMG-CoA reductase inhibitors require clinical monitoring to ensure timely detection of rhabdomyolysis.

Live vaccines should not be used during treatment with everolimus.

Drug interactions

The absorption and subsequent elimination of everolimus may be affected by drugs that interact with CYP3A4 and/or P-glycoprotein. The combined use of everolimus with strong CYP3A4 inhibitors or inducers is not recommended. P-glycoprotein inhibitors may reduce the release of everolimus from intestinal cells and increase everolimus serum concentrations. In vitro, everolimus was a competitive inhibitor of CYP3A4 and CYP2D6, potentially increasing plasma concentrations of drugs eliminated by these enzymes.

The bioavailability of everolimus was significantly increased by concomitant use of cyclosporine (CYP3A4/P-glycoprotein inhibitor).

When studying drug interactions in healthy volunteers who received previous therapy with multiple doses of rifampicin (CYP3A4 inducer), with subsequent use of everolimus in a single dose, an almost 3-fold increase in the clearance of everolimus was observed and a decrease in C max by 58% and AUC by 63% (this combination Not recommended).

Moderate inhibitors of CYP3A4 and P-glycoprotein may increase the concentration of everolimus in the blood, incl. antifungals: fluconazole; macrolide antibiotics (erythromycin); calcium channel blockers (verapamil, nicardipine, diltiazem); protease inhibitors (nelfinavir, indinavir, amprenavir).

Inducers of CYP3A4 may increase the metabolism of everolimus and reduce everolimus blood concentrations, incl. St. John's wort, anticonvulsants (carbamazepine, phenobarbital, phenytoin); drugs for the treatment of HIV (efavirenz, nevirapine).

Grapefruit and grapefruit juice affect the activity of CYP isoenzymes and P-glycoprotein, so consumption of these juices should be avoided while taking everolimus.

Since immunosuppressive drugs may affect the response to vaccination, vaccination may be less effective during treatment with everolimus.

Pharmacotherapeutic group L04AA18 - selective immunosuppressants.

Main Pharmacological action: inhibitor of T-cell activation, prevents allograft rejection in rodent and non-human primate models of allotransplantation; has an immunosuppressive effect by inhibiting the proliferation of T cells activated by a/g (Antigen) and, consequently, clonal expansion driven by interleukins of specific T cells; inhibits intracellular signal transduction, usually leading to cell proliferation when these T-cell growth factors bind to their receptors; blocking this signal with everolimus causes inhibition of cells at the G1 stage of the cell cycle; at the molecular level, the drug forms a complex with the cytoplasmic protein FKBP-12; in the presence of everolimus, growth factor-stimulated p70 S6-kinase phosphorylation is suppressed; the drug completely inhibits the proliferation of hematopoietic cells and non-hematopoietic cells stimulated by growth factors, such as vascular cells of smooth elms; Due to the proliferation of vascular smooth muscle cells stimulated by growth factor, endothelial cells are damaged, which leads to the formation of neointima, which plays a major role in the pathogenesis of chronic disease. (Chronic) rejection.

INDICATIONS: prevention of graft rejection in adult patients with low and moderate immunological risk after allogeneic kidney transplantation BNF (recommendation for the use of drugs in the British National Formulary, issue 60) or heart.

Directions for use and dosage: adults - the initial dose of 0.75 mg 2 times / day (number of times per day), which is recommended for patients who have undergone kidney and heart transplantation, should be used as soon as possible after transplantation; the daily dose should be administered orally 2 times / day (number of times per day ) Dosage adjustment may be necessary for patients, depending on achieved blood levels, tolerability, individual response, changes in concomitant treatment and clinical picture; Dosage adjustments can be made at 4-5 day intervals; use for the treatment of children and adolescents - there are no adequate data, but there is limited information on kidney transplantation in children.

Side effects when using drugs: viral, bacterial and fungal infections, sepsis, wound infection, leukopenia, thrombocytopenia, anemia, coagulopathy, thrombotic thrombocytopenic purpura / hemolytic uremic syndrome (syndrome); hemolysis; hypogonadism in men (low testosterone levels, increased LH) hypercholesterolemia, hyperlipidemia; hypertriglyceridemia; AH (arterial hypertension), lymphocele, venous thromboembolism, pneumonia, pneumonitis; abdominal pain, diarrhea, nausea, vomiting, hepatitis, liver dysfunction, jaundice, changes in liver function tests, acne, surgical complication of a wound, rash, myalgia, urinary tract infections, renal tubular necrosis, pyelonephritis, edema, pain.

Contraindications to the use of drugs: hypersensitivity to the drug.

Drug release forms: table (Tablets) dispersed 0.1 mg, 0.25 mg tablet. (Tablets) 0.25, 0.5 mg, 0.75 mg, 1 mg.

Visamodia with other drugs

The bioavailability of everolimus was increased with cyclosporine. Combination with rifampicin is not recommended. Increase the level of everolimus in the blood: antifungal agents: fluconazole, macrolide a/b: erythromycin, calcium channel blockers: verapamil, nicardipine, diltiazem; protease inhibitors: nelfinavir, indinavir, amprenavir. Increase the metabolism of everolimus and reduce the levels of everolimus in the blood: St. John's wort, anticonvulsants: carbamazepine, phenobarbital, phenytoin, anti-HIV drugs: efavirenz, nevirapine. Grapefruit and grapefruit juice should be avoided. Vaccinations given during treatment may be less effective. The use of live vaccines should be avoided.

Features of use in women during pregnancy and lactation

Pregnancy Should not be prescribed unless the potential benefit outweighs the potential risk to the fetus.
Lactation: Stop breastfeeding during treatment.

Features of use for insufficiency of internal organs

Dysfunction of the cerebrovascular system: No special recommendations
Dysfunction of the liver: Reduce and titrate dose if insufficient.
Renal dysfunction Monitor function, with caution when administered with other drugs.
Respiratory system dysfunction: No special recommendations

Features of use in children and the elderly

children under 12 years old: No application data available
Elderly and senile persons: There are differences compared to younger patients.

Application measures

Information for the doctor: Increases the risk of developing lymphomas or other new malignancies. Excessive suppression of the immune system makes patients prone to infections, especially those caused by opportunistic microorganisms. Weigh the benefits and risks of continuing therapy in patients with severe persistent hyperlipidemia. Regular monitoring of renal function is recommended. Contraindicated in patients with hereditary problems of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption.
Patient information: Women of childbearing potential use contraceptive methods during therapy and for 8 weeks after stopping treatment. Patients should be screened for skin lesions, limit exposure to sunlight and UV radiation, and use appropriate sunscreen.