Everolimus is a new generation antitumor drug. Everolimus - instructions for use, doses, side effects, contraindications, price, where to buy - geotar medicinal reference book Use for renal dysfunction

Everolimus is a chemical agent used to combat the development of malignant tumors.

Release forms, composition and packaging

Everolimus is available in tablet form with different quantitative compositions of the active substance: 2.5 mg, 5 mg and 10 mg.

The drug is known under the brand name "Afinitor" with the active substance everolimus.

The tablets are packaged in cardboard boxes in the amount of 3, 6 or 9 blisters, which contain 10 tablets of white or yellowish (cream) shades.

Afinitor tablets are oblong, flat. On one side of the tablet there is an engraving “NBR”.

The second side is an identification mark for the quantitative content of everolimus:

2.5 mg tablets are engraved “LCL”;
5 mg tablets are engraved with “5”;
10 mg tablets are engraved “UHE”.

In addition to everolimus, tablets with different contents of the active substance include excipients:

dried lactose – from 71.875 mg (1 part) to 287.5 mg (4 parts);
crospovidone - from 25 mg to 100 mg (proportions 1:4 are maintained);
magnesium stearic – from 0.625 mg to 2.5 mg (same proportions);
hypromellose (proportional) – 22.5 mg – 90 mg;
toluene derivative with replacement of two hydrogen atoms in the benzene ring by a butyl radical and a hydroxo group – 0.055 mg – 0.22 mg;
lactose in crystalline monohydrate form – 2.45 mg – 9.8 mg.

Manufacturer

The manufacturer of all drugs containing everolimus (Afinitor and Certican) is the Swiss pharmaceutical company Novartis Pharma AG.

Indications for use

In case of low effectiveness of therapeutic agents in the treatment of many forms of malignant neoplasms with metastases to other organs or their absence, drugs with everolimus are prescribed.

Practice shows the effectiveness of the drug in the treatment of malignant neoplasms of a neuroendocrine nature in and organs of the digestive system.

After exposure to hormonal agents, everolimus in combination with an aromatase inhibitor can effectively influence malignant cells. The drug is best used for the hormone-dependent form in postmenopausal patients.

If there are no urgent indications for surgical resection of renal angiomyolipoma, then everolimus is included in the treatment regimen provided that renal angiomyolipoma is associated with tuberous sclerosis. Tuberous sclerosis is also an indication for the use of everolimus in the diagnosis of subependymal giant cell astrocytomas.

Mandatory conditions for the use of everolimus in the latter case are age at least 3 years and the absence of the possibility of surgical resection of the tumor.

Contraindications

Drugs with everolimus are not used for subependymal giant cell astrocytoma with liver burden according to the Child-Pugh classification of 5-15 points (Child A, B and C) in patients 3-18 years old.

For patients over 18 years of age, everolimus preparations are not applicable with hepatic impairment of 10 to 15 points according to the Child-Pugh classification. Age restrictions for the use of everolimus are the junior preschool period (nursery) with the subependymal nature of giant cell astrocytomas.

In the absence of subependymal giant cell astrocytomas, everolimus-containing drugs should not be prescribed to patients under 18 years of age.

Everolimus should not be prescribed during pregnancy and lactation. If individual intolerance is detected not only to everolimus, but also to any rapamycin derivative. A universal contraindication is the patient’s hypersensitivity to the excipients of the drug for better absorption of everolimus.

Mechanism of action of Everolimus

Everolimus is a protein tyrosine kinase inhibitor that has an immunosuppressive effect on the proliferation of malignant cells.

Indirect inhibition of proliferation is associated with an initial effect on T-lymphocyte-binding antigen. Further, specific T lymphocytes (interleukin-2 and interleukin-15) exhibit inhibition of proliferation, which stops clonal expansion.

Inhibition of reactions is also associated with the intracellular method of signal transmission of the proliferation mechanism, blocking the corresponding receptors. Proliferation stops at the interphase stage, during the presynthetic period G1.

The molecular level of the mechanism of action of everolimus is associated with the formation of the everolimus-protein FKBP-12 complex. The mentioned protein is localized in the cytoplasm of cells. The effect of everolimus is associated with inhibition of the ATP formation reaction by the p70 S6 kinase enzyme.

In turn, p70 S6 kinase is formed due to an enzymatic reaction with the participation of the m-TOR protein. For this reason, the initial inhibition of proliferation reactions is associated with blocking the activity of the m-TOR protein.

Although the mechanism of action of everolimus is different from the pharmacodynamics of cyclosporine with similar effectiveness, the combined use of the two drugs has a more reliable effect on the proliferation of affected cells, which has been shown in allotransplantation models.

In addition to the T-lymphocyte proliferation pathway, the effect of everolimus on cells not associated with hematopoiesis (smooth muscle cells of internal organs) was revealed. The pathogenesis of chronic rejection of former endothelial cells found in the neointima lesion area is also explained by proliferative changes.

Fibroblasts, endothelial cells, blood vessel myocytes, and tumor cells are sensitive to the effects of everolimus on the growth factor during proliferation.

In patients with renal cancer who underwent m-TOR protein inhibition with everolimus, death was prevented in 67 out of 100 cases, which is confirmed by the degree of significance using the Student's t-table.

There was no progression of disease in these forms of cancer after using everolimus for 5 months. More than a third of patients stopped their cancer progression for 6 months after taking everolimus.

Instructions for use

Everolimus is taken 1 tablet per day, preferring the morning (on an empty stomach or after taking a lipid-free meal).

Taking the tablet should be completed by drinking cold purified water. It is not allowed to take the tablet by chewing, crushing or otherwise violating its integrity.

If the patient is physically unable to take the tablet, place it in a glass of cold water, dissolve it thoroughly and drink it. After taking the everolimus solution, pour water into a glass and drink it, carrying with it the remaining active substance and providing the desired concentration of the solution suitable for absorption in the stomach.

The treatment regimen for everolimus is individual: the drug is discontinued after the disappearance of clinical symptoms or the appearance of signs of poor tolerance to toxicity.

For most cancers, the usual daily dose is 10 mg taken as a single dose. If severe toxic reactions develop, the dosage of everolimus is reduced by 2 times or further use of the drug is discontinued.

In patients with subependymal giant cell astrocytoma, the dosage is calculated starting at 4.5 mg/m2. The body surface is calculated using the Dubois formula.

In the absence of toxic reactions, the concentration of everolimus in the blood is determined 2 weeks after the first dose. The concentration should not exceed 15 ng/ml, but should not be less than 3 ng/ml. When the concentration of everolimus is below 3 ng/ml, the dosage of the drug is increased.

Side effects

The drug has side effects on almost all functional systems of the body. The degree of manifestation of the side effect should be assessed by the attending physician and the treatment regimen should be adjusted in a timely manner.

Overdose

Although no cases of overdose have been reported, treatment following an overdose of everolimus should be aimed at eliminating symptoms of overdose. A dose of everolimus not exceeding 70 mg per day is well tolerated by the body.

Special instructions

Kidney function is monitored continuously during the treatment period. If a high concentration of daily creatinine is detected in the patient’s urine, the treatment regimen is adjusted by reducing the dosage of cyclosporine.

During daily monitoring of urine analysis, the stability of taking the rapamycin derivative is monitored.

Compatibility

It should be noted that vaccination while taking everolimus is undesirable due to a decrease in the effectiveness of the procedure.

Drugs for the treatment of AIDS (nevirapine, efavirenz) are incompatible with the simultaneous use of everolimus. Some phytotherapeutic agents (St. John's wort) can reduce the concentration of the active substance.

The opposite effect is observed with the use of calcium channel blockers (nicardipine), antifungal agents (fluconazole), macrolide antibiotics (azithromycin), and protease inhibitors (amprenavir).

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).

Pharmacological action

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 from 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.

Description of the active component

Pharmacological action

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).

Indications

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 difficult-to-tolerate 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 occur 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.

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%).

Contraindications

Hypersensitivity to everolimus, sirolimus.

Pregnancy and lactation

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.

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

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 hepatic impairment, 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.

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

Side effect

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.

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.

Use for liver dysfunction

Use for renal impairment

Special instructions

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.

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

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.

Active ingredient

Everolimus

Release form, composition and packaging

Pills white to white with a yellowish tint, flat, oblong, chamfered, embossed "NVR" on one side and "LCL" on the other.

Excipients: lactose anhydrous - 71.875 mg, crospovidone - 25 mg, hypromellose - 22.5 mg, lactose monohydrate - 2.45 mg, magnesium stearate - 0.625 mg, butylated hydroxytoluene - 0.055 mg.

Pills white to white with a yellowish tint, flat, oblong, chamfered, embossed "NVR" on one side and "5" on the other.

Excipients: anhydrous lactose - 143.75 mg, crospovidone - 50 mg, hypromellose - 45 mg, lactose monohydrate - 4.9 mg, magnesium stearate - 1.25 mg, butylated hydroxytoluene - 0.11 mg.

10 pcs. - blisters (3) - cardboard packs.

Pills white to off-white in color, flat, oblong, chamfered, embossed "NVR" on one side and "UHE" on the other.

Excipients: anhydrous lactose - 287.5 mg, crospovidone - 100 mg, hypromellose - 90 mg, lactose monohydrate - 9.8 mg, magnesium stearate - 2.5 mg, butylated hydroxytoluene - 0.22 mg.

10 pcs. - blisters (3) - cardboard packs.
10 pcs. - blisters (6) - cardboard packs.
10 pcs. - blisters (9) - cardboard packs.

Pharmacological action

Antitumor drug, inhibitor of proliferative signal transmission.

Everolimus is a selective inhibitor of serine-threonine kinase mTOR (mammalian target of rapamycin), specifically affecting the mTORC1 complex of signal-transforming mTOR kinase and regulatory associated protein of mTOR. The mTORC1 complex is a critical regulator of protein synthesis in the distal part of the PI3K/AKT-dependent cascade, which is dysregulated in most human cancers. Everolimus exhibits its activity through high-affinity interaction with the intracellular receptor protein FKBP12. The FKBP12-everolimus complex binds to mTORC1, inhibiting its signaling ability.

The signaling function of mTORC1 is realized through modulating the phosphorylation of distal effectors, of which the most fully characterized translation regulators are ribosomal protein S6 kinase (S6K1) and eukaryotic cell elongation factor 4E-binding protein (4E-BP1). Impaired function of S6K1 and 4E-BP1 due to mTORC1 inhibition impairs the translation of mRNA-encoded essential proteins involved in the regulation of the cell cycle, glycolysis, and cell adaptation to low oxygen levels (hypoxia). This suppresses tumor growth and the expression of hypoxia-inducible factors (eg, the transcription factor HIF-1). The latter leads to a decrease in the expression of factors that enhance the processes of angiogenesis in the tumor (for example, vascular endothelial growth factor - VEGF). Signaling through mTORC1 is regulated by tumor suppressor genes: tuberous sclerosis genes 1 and 2 (TSC1, TSC2). In tuberous sclerosis, a genetically determined disease, inactivating mutations in one or both TSC1 and TSC2 genes lead to the formation of multiple hamartomas of different localizations.

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

Within 6 months, 36% of patients receiving everolimus did not experience disease progression.

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).

When everolimus or placebo was administered to patients with advanced and/or metastatic neuroendocrine tumors, progression-free survival at 18 months was 34.2% versus 8.9%. In patients with advanced and/or metastatic neuroendocrine tumors of the lung or gastrointestinal tract who received long-acting in combination with everolimus or placebo, progression-free survival at 18 months reached 47.2% and 37.4%, respectively.

Activation of the mTOR signaling pathway is a key adaptive mechanism for the development of resistance to endocrine therapy in patients with breast cancer. Various signal transduction pathways are activated during the development of resistance to endocrine therapy. The main one is the PI3K/AKT/mTOR pathway, which is activated in breast cancer cells that are primarily resistant or have lost sensitivity to endocrine therapy with aromatase inhibitors or antiestrogenic drugs. Studies have shown that the mTOR inhibitor everolimus (RAD001) in breast cancer with activation of the PI3K/AKT/mTOR pathway can restore tumor sensitivity to endocrine therapy. Combination therapy with everolimus and an aromatase inhibitor can increase progression-free survival by 2.6 times and, accordingly, reduce the likelihood of disease progression and death by 64%.

Administration of everolimus to patients with angiomyolipoma of the kidney/kidney associated with tuberous sclerosis leads to a statistically significant reduction in the volume of the tumor and to a slowdown in the progression of angiomyolipoma.

In patients with subependymal giant cell astrocytomas (SEGA) associated with tuberous sclerosis, after 6 months of treatment with everolimus, a statistically significant decrease in tumor volume was observed, with 75% of patients having a tumor volume reduced by at least 30%, and in 32% by at least than 50%. At the same time, there were no new lesions, increased hydrocephalus, signs of increased intracranial pressure, or the need for surgical treatment of SEGA.

Pharmacokinetics

Suction

After taking the drug orally in doses of 5 to 70 mg (on an empty stomach or with a small amount of low-fat food), the Cmax of everolimus in the blood is achieved within 1-2 hours. When taking the drug from 5 to 10 mg daily or weekly, the Cmax in the blood changes in proportion to the dose . When everolimus is taken at doses of 20 mg per week or higher, the increase in C max occurs to a lesser extent, however, AUC values increase proportionally to the dose when taking from 5 mg to 70 mg of the drug.

When taking Afinitor at a dose of 10 mg with a high-fat meal, a decrease in C max and AUC of the drug was observed by 54% and 22%, respectively. Low-fat meals reduced Cmax and AUC by 42% and 32%, respectively. However, food intake did not have a significant effect on everolimus elimination rates.

Distribution

The percentage of everolimus concentrations in the blood and in the blood, which is dependent on its concentration in the range from 5 to 5000 ng/ml, varies from 17% to 73%. The plasma concentration of everolimus is approximately 20% of its blood concentration at the concentrations recorded in the blood of cancer patients taking Afinitor at a dose of 10 mg/day.

Plasma protein binding is approximately 74% in both healthy volunteers and patients with moderately impaired liver function.

Experimental studies have shown that after intravenous administration, the permeability of everolimus through the BBB depends on the dose nonlinearly, which suggests saturation of the BBB pump, which ensures that the drug reaches the brain tissue from the blood. The penetration of everolimus through the BBB has also been shown in animals when the drug is administered orally.

After daily or weekly dosing of everolimus, AUC 0-t values were dose proportional at doses of 5 to 10 mg daily and 5 to 70 mg weekly. Steady-state was achieved within 2 weeks with daily dosing of everolimus. C max of everolimus was dose proportional when taking the drug in doses of 5 to 10 mg per day or per week. At doses of 20 mg per week and higher, the increase in Cmax was less pronounced. Tmax in blood plasma was 1-2 hours. With daily administration of everolimus, upon reaching an equilibrium state, there was a significant correlation between the AUC 0-t value and the concentration of the drug in the blood before taking the next dose. T1/2 of everolimus is about 30 hours.

Metabolism

Everolimus is a substrate of CYP3A4 and P-glycoprotein. After oral administration of the drug, everolimus circulates mainly unchanged in the blood. In human blood, 6 main metabolites of everolimus have been identified: 3 monohydroxylated metabolites, 2 open-ring hydrolytic conversion products and everolimus phosphatidylcholine conjugate. These metabolites were approximately 100 times less active than everolimus, so it is generally accepted that most of the total pharmacological activity of everolimus is due to the action of the unchanged substance.

Removal

After a single dose of radiolabeled everolimus was administered to patients, 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.

Pharmacokinetics in special clinical situations

In patients with impaired liver function, when taking everolimus, the systemic exposure of the drug increases by 1.6, 3.3 and 3.6 times, respectively, with liver failure of mild severity (Child-Pugh class A), moderate severity (Child-Pugh class B) and severe (class C according to the Child-Pugh classification). Dose adjustment of everolimus is necessary if liver function is impaired.

There was no significant effect of creatinine clearance (from 25 to 178 ml/min) on the clearance of everolimus in patients with progressive solid tumors. Post-transplant renal dysfunction (creatinine clearance from 11 to 107 ml/min) did not affect the pharmacokinetics of everolimus in patients after organ transplantation.

The use of everolimus in children and adolescents under 18 years of age according to the following indications: advanced and/or metastatic renal cell cancer and advanced and/or metastatic neuroendocrine tumors of the gastrointestinal tract, lung and pancreas, hormone-dependent advanced breast cancer, renal angiomyolipoma associated with tuberous sclerosis, contraindicated.

In patients with SEGA, the individual steady-state minimum therapeutic concentration (C min) of everolimus was directly proportional to the daily dose and ranged from 1.35-14.4 mg/m2.

In patients with SEGA, the geometric mean C min of everolimus normalized to the dose in mg/m2 in patients under 10 years of age and from 10 to 18 years of age is statistically significantly lower than in adult patients, which may indicate increased clearance of everolimus in young patients.

There was no significant effect of patient age (from 27 to 85 years) on the clearance of everolimus (from 4.8 to 54.7 l/h) after oral administration.

After oral administration of the drug, the clearance of everolimus does not differ between Caucasian and Mongoloid individuals with similar liver function. According to a population pharmacokinetic analysis, in people of the Negroid race after organ transplantation, when taking the drug orally, the clearance of everolimus was on average 20% greater than in representatives of the Caucasian race.

There was some correlation between the decrease in 4E-BP1 phosphorylation in tumor tissue and the C min of everolimus in the blood at steady state after daily dosing of the drug at a dose of 5 mg or 10 mg.

Additional evidence suggests that the reduction in S6 kinase phosphorylation is highly sensitive to mTOR inhibition by everolimus. Suppression of phosphorylation of the translation initiation factor eIF-4G was complete at all C min values of everolimus determined in the blood when taking the drug daily at a dose of 10 mg.

In patients with SEGA, it was shown that a 2-fold increase in C min leads to a decrease in tumor size by 13%, while a decrease in tumor size by 5% is considered statistically significant.

Indications

- advanced and/or metastatic renal cell carcinoma with ineffective antiangiogenic therapy;

- widespread and/or metastatic neuroendocrine tumors of the gastrointestinal tract, lung and pancreas;

- hormone-dependent advanced breast cancer in postmenopausal patients, in combination with an aromatase inhibitor, after previous endocrine therapy;

— subependymal giant cell astrocytomas associated with tuberous sclerosis in patients over 3 years of age when surgical resection of the tumor is impossible;

- renal angiomyolipoma associated with tuberous sclerosis, which does not require immediate surgical intervention.

Contraindications

- liver dysfunction classes A, B, C according to the Child-Pugh classification in patients aged 3 to 18 years with subependymal giant cell astrocytomas;

- impaired liver function class C according to the Child-Pugh classification in patients over 18 years of age with subependymal giant cell astrocytomas;

- pregnancy;

- lactation period (breastfeeding);

- age up to 3 years (subependymal giant cell astrocytomas);

- age up to 18 years (with the exception of subependymal giant cell astrocytomas);

- simultaneous use of everolimus with strong inducers of the CYP3A4 isoenzyme or inducers of P-glycoprotein;

- hypersensitivity to the components of the drug;

- hypersensitivity to other rapamycin derivatives.

WITH caution the drug should be used simultaneously with moderate CYP3A4 inhibitors or P-glycoprotein inhibitors; in patients before surgery (since the use of rapamycin derivatives, including Afinitor, may slow down the wound healing process); in patients with lactose intolerance, severe lactase deficiency or glucose-galactose malabsorption.

Afinitor is not recommended for use in severe liver failure (Child-Pugh class C) unless the benefits of drug therapy outweigh the possible risks (for all indications except subependymal giant cell astrocytomas).

Dosage

Afinitor should be taken orally 1 time/day every day at the same time (preferably in the morning) on an empty stomach or after eating a small amount of food that does not contain fat. The tablets should be swallowed whole with a glass of water and should not be chewed or crushed. If patients, for health reasons, cannot swallow the tablet whole, it is recommended that Afinitor be completely dissolved in a glass of water (approximately 30 ml), stirring gently, immediately before taking. After taking the glass, it is recommended to rinse the glass with the same amount of water and drink the resulting solution to ensure that the full dose of the drug is taken.

Treatment with the drug is carried out as long as the clinical effect remains and there are no signs of intolerable toxicity.

Advanced and/or metastatic renal cell carcinoma if ineffective antiangiogenic therapy, advanced and/or metastatic neuroendocrine tumors of the gastrointestinal tract, lung and pancreas, hormone-dependent advanced breast cancer, renal angiomyolipoma not requiring immediate surgical intervention in patients with tuberous sclerosis

The recommended dose of Afinitor is 10 mg 1 time / day. If severe and/or intractable adverse reactions develop, the dose of Afinitor should be reduced by 50% and/or temporarily discontinue drug therapy until the clinical symptoms of adverse reactions resolve, followed by restoration of the drug at the original dose.

Severity 1	Recommendations for changing the dose and correcting adverse reactions 2
Non-infectious pneumonitis
Degree 1	No dose change is required. Condition monitoring.
Degree 2	Discontinue therapy with Afinitor, exclude an infectious process, and, if necessary, prescribe GCS until symptoms are reduced to grade 1. Resumption of therapy with Afinitor at a reduced dose. Discontinue therapy with Afinitor if symptoms do not improve to grade 1 within 3 weeks.
Degree 3	Discontinue therapy with Afinitor until symptoms decrease to grade 1, exclude an infectious process, and, if necessary, prescribe GCS. Resumption of therapy with Afinitor at a reduced dose.
Degree 4	Discontinue therapy with Afinitor, exclude an infectious process, and, if necessary, prescribe GCS.
Stomatitis
Degree 1	No dose change is required. Rinse your mouth with non-alcohol or water-salt solutions (0.9%) several times a day.
Degree 2	If symptoms of stomatitis re-develop to grade 2, discontinue therapy with Afinitor until symptoms decrease to grade 1. Resumption of therapy with Afinitor at the previous dose. Treatment with analgesics for external use (benzocaine, butylaminobenzoate, tetracaine hydrochloride, menthol or phenol) with or without corticosteroids for external use 3.
Degree 3	Discontinue therapy with Afinitor until symptoms decrease to grade 1. Resumption of therapy with Afinitor at a reduced dose. Treatment with analgesics for external use (benzocaine, butylaminobenzoate, tetracaine hydrochloride, menthol or phenol) with or without corticosteroids for external use 3.
Degree 4	Discontinuation of Afinitor therapy. Treatment of stomatitis with appropriate methods.
Other non-hematological toxicities (excluding metabolic disorders)
Degree 1
Degree 2	No dose change is required if symptoms are tolerated. Treatment with appropriate methods and monitoring of the condition. If symptoms are intolerable, discontinue therapy with Afinitor until symptoms decrease to grade 1. Resumption of therapy with Afinitor at the previous dose.
Degree 3	Discontinue therapy with Afinitor until symptoms decrease to grade 1. Treatment with appropriate methods and monitoring of the condition. Resumption of therapy with Afinitor at a reduced dose
Degree 4
Metabolic disorders (eg, hyperglycemia, dyslipidemia)
Degree 1	No dose change is required if symptoms are tolerated. Treatment with appropriate methods and monitoring of the condition.
Degree 2	No dose change is required if symptoms are tolerated. Treatment with appropriate methods and monitoring of the condition.
Degree 3	Temporarily discontinue therapy with Afinitor. Resumption of therapy with Afinitor at a reduced dose. Treatment with appropriate methods and monitoring of the condition.
Degree 4	Discontinue therapy with Afinitor and treat with appropriate methods.
1 Severity: 1 = mild symptoms; 2 = moderate symptoms; 3 = severe symptoms; 4 = life-threatening symptoms. 2 If a reduction in the dose of the drug is required, it is recommended to use a dose approximately 50% less than the previous one. 3 Avoid the use of drugs containing hydrogen peroxide, iodine and thyme derivatives in the treatment of stomatitis (they may provoke increased ulceration in the oral cavity).

When used concomitantly with moderate CYP3A4 inhibitors and P-glycoprotein inhibitors, the dose of Afinitor should be reduced by 50%. In patients receiving Afinitor at a dose of 2.5 mg/day, further dose reduction, if necessary, is possible when taking the drug every other day. Further dose reduction may be required if severe and/or intractable adverse reactions develop.

When prescribing Afinitor simultaneously with strong inducers of the CYP3A4 isoenzyme, it may be necessary, based on pharmacokinetic data, to increase the dose from 10 mg to 20 mg/day in increments of 5 mg (once every 7-14 days). It is expected that with this dose change of Afinitor, the AUC value will correspond to the AUC observed without taking the isoenzyme inducers, however, there are no clinical data with such a dose change in patients receiving strong CYP3A4 inducers. If you stop taking a powerful inducer of the CYP3A4 isoenzyme, the dose of Afinitor should be returned to the original dose.

Subependymal giant cell astrocytomas (SEGA) associated with tuberous sclerosis in patients over 3 years of age if it is impossible to perform surgical resection of the tumor

Patients receiving everolimus therapy for SEGA should monitor everolimus blood concentrations. Dose titration may be required to achieve optimal therapeutic effect. Dosages that are well tolerated and effective vary from patient to patient. Concomitant therapy may affect the metabolism of everolimus and individual tolerability of the drug.

The initial dose of the drug is determined based on the body surface area calculated using the Dubois formula.

The recommended starting dose of Afinitor for the treatment of patients with SEGA is 4.5 mg/m2, rounded to the nearest Afinitor dosage. Afinitor tablets of various dosages can be combined to obtain the required dose.

Everolimus blood concentrations should be assessed approximately 2 weeks after initiation of treatment. C min of the drug in the blood should be in the range of 3-15 ng/ml. The dose may be increased to achieve higher concentrations within the therapeutic range to achieve optimal efficacy based on tolerability. If the concentration of everolimus is below 3 ng/ml, the dose of the drug can be increased by 2.5 mg/day every 2 weeks, taking into account drug tolerability.

After initiation of Afinitor therapy, SEGA tumor volume should be assessed every 3 months. When individually selecting a dose, the response of the tumor to treatment, the concentration of everolimus in the blood and individual tolerability of the drug should be taken into account.

Correction of severe and/or intractable adverse reactions may require temporary dose reduction or discontinuation of therapy. If a reduction in the dose of the drug is required, it is recommended to use a dose approximately 50% less than the previous one (see Table 1). In patients receiving Afinitor at a dose of 2.5 mg/day, further dose reduction, if necessary, is possible when taking the drug every other day.

When used concomitantly with moderate CYP3A4 inhibitors or P-glycoprotein inhibitors, the dose of Afinitor should be reduced by 50%. Further dose reduction may be required if severe and/or intractable adverse reactions develop. Everolimus concentrations should be monitored 2 weeks after moderate CYP3A4 inhibitors or P-glycoprotein inhibitors are added to therapy. When discontinuing therapy with moderate CYP3A4 inhibitors or P-glycoprotein inhibitors, the dose of Afinitor should be returned to the original dose and the plasma concentration of everolimus should be determined after 2 weeks.

When prescribing Afinitor concomitantly with strong inducers of the CYP3A4 isoenzyme (for example, antiepileptic drugs), an increase in the dose of Afinitor may be required to achieve a therapeutic concentration of 3-15 ng/ml. If the concentration of everolimus is below 3 ng/ml and the drug is well tolerated by the patient, the daily dose can be increased by 2.5 mg every 2 weeks, while the concentration of everolimus in the blood should be monitored. If you stop taking a powerful inducer of the CYP3A4 isoenzyme, the dose of Afinitor should be returned to the original dose, and after 2 weeks the concentration of everolimus in the blood plasma should be determined.

Therapeutic monitoring of everolimus blood concentrations in patients with SEGA

In patients with SEGA, plasma concentrations of everolimus should be monitored using validated bioanalytical liquid chromatography/mass spectrometry methods. Therapeutic monitoring of everolimus concentrations should be carried out 2 weeks after the start of therapy, after any change in the dose of the drug or the addition of inhibitors or inducers of the CYP3A4 isoenzyme to therapy or the appearance of signs of liver dysfunction. C min of everolimus in the blood should be in the range of 3-15 ng/ml. The dose must be titrated until the minimum therapeutic concentration (3-15 ng/ml) is reached, taking into account the patient’s tolerability of therapy. The dose can be increased to achieve a higher concentration of the drug in the blood (in the therapeutic range) and an optimal therapeutic effect, while taking into account the patient's tolerability of the drug.

Patients under 18 years of age

At treatment of SEGA at children and teenagers The recommended doses are the same as for the treatment of adult patients with SEGA.

Patients aged ≥65 years

Patients with impaired renal function

No dose adjustment is required.

Patients with liver dysfunction

At advanced and/or metastatic renal cell carcinoma or metastatic neuroendocrine tumors of the gastrointestinal tract, lung and pancreas, hormone-dependent advanced breast cancer, renal angiomyolipoma associated with tuberous sclerosis at patients with mild liver dysfunction (class A according to the Child-Pugh classification) The recommended dose is 7.5 mg/day. U patients with moderate liver dysfunction (class B according to the Child-Pugh classification) The recommended dose is 2.5 mg/day. U patients with severe liver dysfunction (class C according to the Child-Pugh classification) the drug is not recommended. In cases where the potential benefit outweighs the risk, everolimus can be taken at a maximum dose of 2.5 mg/day.

For subependymal giant cell astrocytomas associated with tuberous sclerosis Afinitor patients over 18 years of age with mild liver dysfunction (class A according to the Child-Pugh classification):- 75% of the dose calculated by body surface area (rounded to the nearest dosage). At liver dysfunction of moderate severity (class B according to the Child-Pugh classification):- 25% of the dose calculated by body surface area (rounded to the nearest dosage). At severe liver dysfunction (class C according to the Child-Pugh classification): treatment with the drug is contraindicated.

Everolimus whole blood concentrations should be determined approximately 2 weeks after initiation of treatment or after any change in liver function (Child-Pugh classification). The dose should be titrated to achieve drug concentrations in the range of 3 to 15 ng/ml. The dose may be increased to achieve higher concentrations within the therapeutic range to achieve optimal efficacy based on tolerability. If the concentration of everolimus is below 3 ng/ml, the dose of the drug can be increased by 2.5 mg/day, taking into account the tolerability of the drug.

Side effects

Advanced and/or metastatic renal cell carcinoma or metastatic neuroendocrine tumors of the gastrointestinal tract, lung and pancreas, hormone-dependent advanced breast cancer

When using the drug, the most common adverse reactions (frequency ≥10%) were (in descending order of frequency): stomatitis, skin rash, diarrhea, fatigue, infections, asthenia, nausea, peripheral edema, loss of appetite, headache, pneumonitis, change taste perception, nosebleeds, inflammation of the mucous membranes, vomiting, itching, cough, shortness of breath, dry skin, nail damage and increased body temperature. The most common grade 3-4 adverse reactions (incidence ≥2%) were: stomatitis, fatigue, diarrhea, infections, pneumonitis and diabetes mellitus.

<1/10), нечасто (≥1/1000 и <1/100), редко (≥1/10 000 и <1/1000), очень редко (<1/10 000), включая отдельные сообщения.

Metabolism and nutrition: very often - loss of appetite, loss of body weight; often - dehydration.

From the endocrine system: often - exacerbation of existing diabetes mellitus; infrequently - newly diagnosed diabetes mellitus.

From the cardiovascular system: often - bleeding, increased blood pressure; uncommon - deep vein thrombosis, chronic heart failure.

From the nervous system: very often - changes in taste perception, headache, dizziness; infrequently - loss of taste sensitivity.

From the mental side: often - insomnia.

From the side of the organ of vision: often - conjunctivitis, swelling of the eyelids.

very often - cough, pneumonitis (including alveolitis, interstitial lung disease, alveolar pulmonary hemorrhage, pulmonary infiltration, pulmonary toxicity), epistaxis, shortness of breath; often - pulmonary embolism, hemoptysis; infrequently - acute respiratory distress syndrome.

very often - stomatitis (including aphthous stomatitis and ulceration of the tongue and oral mucosa), diarrhea, nausea, vomiting; often - dry mouth, pain in the oral cavity, abdominal pain, dyspepsia, dysphagia.

From the musculoskeletal system: often - arthralgia.

often - proteinuria, renal failure, frequent urination during the day.

very often - rash, dry skin, itching, damage to the nail plates; often - acne, palmoplantar erythrodysesthesia syndrome, erythema.

infrequently - true erythrocyte aplasia of the bone marrow.

General violations: very often - increased fatigue, asthenia, inflammation of the mucous membranes, peripheral edema, increased body temperature, decreased body weight; often - chest pain; infrequently - slow healing of wounds.

Allergic reactions: When using everolimus, cases of hypersensitivity, manifested by anaphylactic reactions, shortness of breath, flushing, chest pain or angioedema (for example, swelling of the airways and tongue with or without breathing problems), have been reported.

≥ 10% (in descending order) - decreased hemoglobin, lymphopenia, leukopenia, neutropenia, thrombocytopenia; increased concentrations of cholesterol, triglycerides, glucose, increased AST activity, increased creatinine, increased ALT activity, increased serum bilirubin, hypophosphatemia and hypokalemia. Most laboratory abnormalities were mild to moderate. Severe (grade 4) abnormalities included lymphopenia (2.2%), decreased hemoglobin (2%), hypokalemia (2%), neutropenia (<1%), тромбоцитопению (<1%), гипофосфатемию (<1%), а также повышение креатинина (1%), холестерина (<1%), активности ACT (<1%), АЛТ (<1%), билирубина (<1%), глюкозы (<1%) в сыворотке крови.

Subependymal giant cell astrocytomas

Clinical trial data (average duration of therapy - 9.6 months)

Most common (≥ 10%): stomatitis.

Grade 3 adverse reactions (≥ 2%) were represented by stomatitis, neutropenia, and viral gastroenteritis. No grade 4 adverse reactions were recorded.

Determination of the frequency of adverse reactions when using the drug Afinitor: very often (≥1/10), often (≥1/100 and< 1/10), нечасто (≥ 1/1000 и <1/100), редко (≥ 1/10 000 и < 1/1000), очень редко (< 1/10 000), включая отдельные сообщения.

From the respiratory system: often - cough, nosebleeds, pneumonitis.

From the hematopoietic system: often - neutropenia, anemia.

From the digestive system: very often - stomatitis (includes ulceration of the oral mucosa, lips); often - pain in the mouth, gastritis, vomiting.

For the skin and subcutaneous tissues: often - rash (includes maculopapular rash, macular rash, generalized rash).

From the nervous system: often - convulsions.

Mental disorders: often - aggressiveness, insomnia.

Common disorders: often - fatigue, irritability, increased body temperature, gait disturbances.

From the reproductive system: often - amenorrhea, irregular menstrual cycle.

often - increased concentration of triglycerides in the blood, increased concentration of total cholesterol in the blood plasma, increased LDL levels.

Deviations in laboratory and instrumental parameters observed with a frequency of ≥10% (in descending order): hematological - increased aPTT, decreased absolute neutrophil count, anemia; biochemical - hypercholesterolemia, increased AST activity, hypertriglyceridemia, increased ALT activity, hypophosphatemia, hypokalemia.

Most of the above adverse reactions were mild (1) or moderate (2) in severity.

There were cases of decrease in the absolute number of neutrophils of grade 3.

Data from a phase 2 clinical trial (average treatment duration - 34 months).

The adverse reactions described below were observed only in phase 2 clinical studies.

For the skin and subcutaneous tissues: very often - acneiform dermatitis, acne, furunculosis.

From the digestive system: very often - diarrhea, often - vomiting, gastritis.

From the side of the organ of vision: very often - conjunctivitis.

From the urinary system: often - proteinuria.

Laboratory and instrumental data: often - a decrease in the concentration of immunoglobulin G in the blood.

Deviations in laboratory and instrumental parameters observed with a frequency of ≥ 10%: hematological - leukopenia, thrombocytopenia, lymphopenia; biochemical - increased alkaline phosphatase activity, increased glucose and creatinine concentrations, decreased glucose concentrations. There were cases of increased AST activity, grade 3 alkaline phosphatase and a decrease in the absolute number of neutrophils and lymphocytes of grade 4 severity.

Renal angiomyolipoma not requiring immediate surgical intervention in patients with tuberous sclerosis

Most often (frequency ≥1/10%): stomatitis, hypercholesterolemia, acne, fatigue, anemia, increased LDH activity in the blood plasma, leukopenia and nausea. The most common adverse reactions of grade 3-4 severity (frequency ≥ 2%): stomatitis, amenorrhea. One death was reported in a patient receiving Afinitor; death was a consequence of status epilepticus. There was no association between the cause of death and the use of Afinitor.

Determination of the frequency of adverse reactions that occurred when taking the drug Afinitor at a dose of 10 mg/day: very often (≥1/10), often (≥1/100 and<1/10), нечасто (≥1/1000 и <1/100), редко (≥1/10 000 и <1/1000), очень редко (<1/10 000), включая отдельные сообщения.

From the hematopoietic system: very often - anemia, leukopenia; often - thrombocytopenia.

From the side of metabolism: often - loss of appetite.

From the nervous system: often - headache, change in taste perception, loss of taste sensitivity.

From the respiratory system: often - cough, pneumonitis, nosebleeds.

From the digestive system: very often - stomatitis (including aphthous stomatitis and ulceration of the tongue and oral mucosa), nausea; often - diarrhea, vomiting, abdominal pain, flatulence.

For the skin and subcutaneous tissues: very often - acne, often - acneiform dermatitis, dry skin, papules.

From the reproductive system: often - amenorrhea, irregular menstrual cycle, uterine bleeding, vaginal bleeding, opsomenorrhea.

General violations: very often - increased fatigue.

From the immune system: often - hypersensitivity reactions.

From the urinary system: often - acute renal failure.

From the laboratory parameters: very often - increased LDH activity; often - hypophosphatemia, hyperlipidemia, iron deficiency; ≥10% (in descending order) - decreased hemoglobin in the blood serum, leukopenia, neutropenia, thrombocytopenia, hypercholesterolemia, hypertriglyceridemia, increased activity of AST, ALT, increased concentrations of glucose, bilirubin in the blood, decreased phosphorus levels in the blood serum. Most of the above adverse reactions were mild (grade 1) or moderate (grade 2). The most common laboratory abnormalities of grade 3-4 are hypophosphatemia (5.1%), hypofibrinogenemia (2.5%), lymphopenia (1.3%) and neutropenia (1.3%), increased alkaline phosphatase activity (1.3%), AST (1.3%), ALT (1.3%), hyperkalemia (1.3%).

Adverse reactions of particular clinical interest

In clinical studies, when using the drug, there were cases of exacerbation of viral hepatitis B, including cases with a fatal outcome. Worsening infections are expected during periods of immunosuppression.

When using everolimus, according to clinical studies and spontaneous reports during post-marketing observation, cases of renal failure (including death) and proteinuria were observed.

When using everolimus, according to clinical studies and spontaneous reports registered in the post-marketing period, cases of amenorrhea (including secondary amenorrhea) were observed.

Overdose

No cases of drug overdose have been reported. With a single oral dose of the drug in doses up to 70 mg, its tolerability was satisfactory.

Treatment: in case of overdose, it is necessary to monitor the patient and prescribe appropriate symptomatic therapy.

Drug interactions

Everolimus is a substrate of the CYP3A4 isoenzyme, as well as a substrate and moderately active inhibitor of P-glycoprotein, which ensures the release of many drug compounds from cells. Therefore, the absorption and subsequent elimination of everolimus may be affected by substances that interact with CYP3A4 and/or P-glycoprotein.

In vitro, everolimus exhibits properties as a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6.

Drugs that can increase the concentration of everolimus in the blood

The concentration of everolimus in the blood may increase when used simultaneously with drugs that are inhibitors of the CYP3A4 isoenzyme (reduced metabolism of everolimus) or P-glycoprotein (reduced release of everolimus from intestinal cells). Concomitant use of everolimus with strong inhibitors of CYP3A4 or P-glycoprotein (including ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, clarithromycin, nefazodone, ritonavir, atazanavir, saquinavir, darunavir, indinavir, nelfinavir and other drugs with similar activity) should be avoided.

The systemic bioavailability of everolimus increased significantly (increase in Cmax and AUC by 4.1 and 15.3 times, respectively) in healthy volunteers when everolimus was co-administered with ketoconazole, which is a potent inhibitor of CYP3A4 and P-glycoprotein.

Caution is required when administering everolimus concomitantly with moderate CYP3A4 inhibitors (including erythromycin, verapamil, cyclosporine, fluconazole, diltiazem, amprenavir, fosamprenavir or aprepitant) or P-glycoprotein inhibitors.

When used concomitantly with moderate CYP3A4 inhibitors or P-gp inhibitors, the dose of Afinitor should be reduced.

The systemic bioavailability of the drug in healthy volunteers increased when used simultaneously with erythromycin (moderately active inhibitor of CYP3A4 and P-glycoprotein; Cmax and AUC of everolimus increased by 2 and 4.4 times, respectively); with verapamil (moderately active inhibitor of CYP3A4 and P-glycoprotein; Cmax and AUC of everolimus increased by 2.3 and 3.5 times, respectively); with cyclosporine (CYP3A4 substrate and P-glycoprotein inhibitor; Cmax and AUC of everolimus increased by 1.8 and 2.7 times, respectively).

Other moderate CYP3A4 and P-glycoprotein inhibitors that may increase everolimus blood concentrations include some antifungals (eg, fluconazole) and some (eg, diltiazem).

There were no differences in the C min of everolimus administered at a daily dose of 5 mg or 10 mg when administered with or without CYP3A4 and/or P-glycoprotein substrates.

Co-administration with weak inhibitors of the CYP3A4 isoenzyme, together with or without P-glycoprotein inhibitors, did not affect the C min of everolimus used at a daily dose of 5 or 10 mg.

Drugs that can reduce the concentration of everolimus in the blood

The concentration of everolimus in the blood may decrease when used with drugs that are inducers of the CYP3A4 isoenzyme (increased metabolism of everolimus) or P-glycoprotein (increased release of everolimus from intestinal cells). Concomitant use of everolimus with strong CYP3A4 inducers or P-gp inducers should be avoided. If it is necessary to use Afinitor together with strong CYP3A4 inducers or P-glycoprotein inducers (for example, rifampicin or rifabutin), the dose of the drug should be increased.

In healthy volunteers who received previous therapy with rifampicin (600 mg/day for 8 days), with subsequent use of everolimus in a single dose, an almost 3-fold increase in the clearance of the latter and a decrease in Cmax by 58% and AUC by 63% were observed.

Other strong inducers of CYP3A4 may also increase the metabolism of everolimus and reduce everolimus blood concentrations (for example, St. John's wort; corticosteroids, including dexamethasone, prednisone, prednisolone; some anticonvulsants - carbamazepine, phenobarbital, phenytoin; drugs for the treatment of HIV - efavirenz , nevirapine).

Effect of everolimus on plasma concentrations of drugs used as concomitant therapy

In healthy volunteers, the simultaneous use of everolimus with atorvastatin (a CYP3A4 substrate) or pravastatin (not a CYP3A4 substrate) did not cause clinically significant pharmacokinetic interactions. A population pharmacokinetic analysis also did not reveal the effect of simvastatin (a CYP3A4 substrate) on the clearance of everolimus.

In vitro, everolimus competitively inhibited the metabolism of cyclosporine (a CYP3A4 substrate) and was a mixed inhibitor of the metabolism of dextromethorphan (a CYP2D6 substrate). The maximum of everolimus is at steady state when taking the drug orally at a dose of 10 mg/day or 70 mg/week. on average was more than 12-36 times lower than the K i values of everolimus for the inhibitory effect in vitro on the CYP3A4 and CYP2D6 isoenzymes. Therefore, an in vivo effect of everolimus on the metabolism of CYP3A4 and CYP2D6 substrates is unlikely.

The combined use of everolimus and midazolam leads to an increase in Cmax of midazolam by 25% and an increase in AUC(0-inf) of midazolam by 30%, while the metabolic ratio AUC (1-hydroxymidazolam/midazolam) and T1/2 of midazolam do not change. This suggests that increased midazolam exposure is a consequence of the GI effects of everolimus when both drugs are administered at the same time. Therefore, everolimus may affect the bioavailability of concomitantly taken orally medicinal products that are substrates of the CYP3A4 isoenzyme. Everolimus is unlikely to alter the exposure of other medicinal products that are CYP3A4 substrates when administered by routes other than orally, such as IV, SC and transdermal routes.

The combined use of everolimus and exemestane leads to an increase in C max and C 2h of the latter by 45% and 71%, respectively. However, the corresponding estradiol levels at steady state (4 weeks) did not differ between the two treatment groups. In postmenopausal patients with hormone-dependent advanced hormone receptor-positive breast cancer who received the appropriate combination, there was no increase in the incidence of side effects. It is unlikely that increased concentrations of exemestane would affect the efficacy and safety of everolimus.

The combined use of everolimus and extended-release octreotide leads to an increase in the C min of octreotide, which has a minor effect on the clinical effect of everolimus in patients with metastatic neuroendocrine tumors.

Other interactions that may affect everolimus concentrations

The simultaneous use of everolimus with grapefruit, grapefruit juice, carambola (tropical star), bitter orange and other products that affect the activity of cytochrome P450 and P-glycoprotein should be avoided.

Vaccination

Immunosuppressants may influence vaccination response; During treatment with Afinitor, vaccination may be less effective. The use of live vaccines should be avoided.

Special instructions

Treatment with Afinitor should only be carried out under the supervision of a physician experienced in working with anticancer drugs.

Before starting treatment with Afinitor and periodically during therapy, renal function should be monitored, including determining the concentration of blood urea nitrogen, urine protein or serum creatinine and performing a clinical blood test (including blood cell counts), as well as monitor drug concentrations in patients with SEGA.

Adequate monitoring of blood glucose concentrations should be ensured before and during treatment with Afinitor.

Non-infectious pneumonitis is a class-specific side effect of rapamycin derivatives. Cases of non-infectious pneumonitis (including interstitial lung disease) have also been reported with the use of Afinitor. In some cases, severe forms of the disease (rarely fatal) were observed. The diagnosis of non-infectious pneumonitis should be assumed when non-specific manifestations of the respiratory system such as hypoxia, pleural effusion, cough or shortness of breath develop, as well as when infectious, tumor and other causes of such manifestations are excluded using appropriate diagnostic studies. Patients should report to their healthcare provider the development of any new or worsening respiratory symptoms. If there are only radiological signs of non-infectious pneumonitis (in the absence of clinically significant symptoms), treatment with Afinitor can be continued without changing the dose. If symptoms of pneumonitis are moderate, temporary interruption of therapy should be considered until symptoms resolve. GCS can be used to relieve symptoms. Treatment with the drug can be resumed at a dose 50% lower than the original one. If severe symptoms of non-infectious pneumonitis (grade 3 or 4) develop, therapy with Afinitor should be discontinued. GCS can be used to relieve symptoms. Depending on the specific clinical conditions, after the pneumonitis has resolved, Afinitor therapy can be resumed at a dose 50% lower than the original dose.

Afinitor has immunosuppressive properties and may contribute to the development of bacterial, fungal, viral or protozoal infections in patients, especially those caused by opportunistic microorganisms. Local and systemic infections, including pneumonia, other bacterial infections, as well as fungal infections such as aspergillosis or candidiasis, and viral infections, including exacerbation of hepatitis B virus, have been described in patients taking Afinitor. Some of these infections were severe (with development of respiratory or liver failure) and sometimes fatal. Patients should be informed of the increased risk of developing infections when using Afinitor and promptly seek medical attention if symptoms of infection occur. Patients with infections should receive appropriate treatment before prescribing Afinitor.

If an invasive systemic fungal infection develops, Afinitor therapy should be discontinued and appropriate antifungal therapy should be instituted.

In patients treated with Afinitor, ulcerative lesions of the oral mucosa, stomatitis and inflammation of the oral mucosa were observed. In such cases, local therapy is recommended, but the use of mouth rinses containing alcohol or alcohol should be avoided, as their use may worsen the condition. Antifungal agents should only be used if a fungal infection is confirmed.

Caution should be exercised when co-administering everolimus and moderate CYP3A4 inhibitors or P-glycoprotein inhibitors.

The simultaneous administration of everolimus and strong inducers of the CYP3A4 isoenzyme should be avoided.

Use in pediatrics

The use of everolimus is contraindicated in children and adolescents under 18 years of age for the following indications: advanced and/or metastatic renal cell carcinoma with ineffective antiangiogenic therapy, advanced and/or metastatic neuroendocrine tumors of the gastrointestinal tract, lung and pancreas, hormone-dependent advanced breast cancer, renal angiomyolipoma associated with tuberous sclerosis.

Impact on the ability to drive vehicles and operate machinery

Studies of the effect of Afinitor on the ability to drive vehicles and operate machinery have not been conducted. Given the possibility of developing some side effects while taking Afinitor (fatigue, dizziness, drowsiness), patients should be careful when driving vehicles and engaging in other potentially hazardous activities that require increased concentration.

No dose adjustment is required. Storage conditions and periods

The drug should be stored out of the reach of children, in a dry place, protected from light, at a temperature not exceeding 30°C. Shelf life - 3 years.