Everolimus is a new generation anticancer drug. Everolimus is a new generation anticancer drug Dosage and administration

Everolimus is an anti-developmental chemical malignant tumors.

Forms of release, composition and packaging

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

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

The tablets are packed 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 is engraved "NBR".

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

• tablets with 2.5 mg are engraved with "LCL";
• tablets with 5 mg are engraved with "5";
• 10 mg tablets are engraved with "UHE".

In addition to everolimus, tablets with different content active substance excipients include:

• dried lactose - from 71.875 mg (1 part) to 287.5 mg (4 parts);
• crospovidone - from 25 mg to 100 mg (1: 4 proportions are preserved);
• stearic magnesium - from 0.625 mg to 2.5 mg (the same proportions);
• hypromellose (in proportion) - 22.5 mg - 90 mg;
• a toluene derivative with the substitution of two hydrogen atoms in the benzene ring for 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 the case of low efficiency of therapeutic agents in the treatment of many forms of malignant neoplasms with or without metastases to other organs, preparations with everolimus are prescribed.

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

When after exposure hormonal drugs effectively affect malignant cells with everolimus in combination with an aromatase inhibitor. The drug is best used in the hormone-dependent form in postmenopausal patients.

If there are no urgent indications for surgical resection of angiomyolipoma of the kidney, then everolimus is included in the treatment regimen, provided that the angiomyolipoma of the kidney 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 the age of 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 hepatic aggravation according to Child-Pugh classification 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 from 10 to 15 points according to the Child-Pugh classification. Age restrictions for the use of everolimus are the younger preschool period (nursery) with the subependymal nature of giant cell astrocytomas.

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

During the period of gestation and the lactation period, everolimus should not be prescribed. When detecting individual intolerance not only to everolimus, but also to any derivative of rapamycin. The universal contraindication is hypersensitivity the patient to the excipients of the drug for better absorption of everolimus.

Everolimus mechanism of action

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

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

Inhibition of reactions is also associated with the intracellular way of signal transmission of the proliferation mechanism, blocking the corresponding receptors. Proliferation stops at the interphase stage, during the presynthetic period G 1 .

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 reaction of ATP formation by the enzyme p70 S6 kinase.

In turn, p70 S6 kinase is formed due to an enzymatic reaction with the participation of the m-TOR protein. The initial inhibition of proliferation reactions for this reason 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 efficacy, 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 pathway of proliferation, the effect of everolimus on cells not associated with hematopoiesis (smooth muscle cells internal organs). The pathogenesis of chronic rejection of former endothelial cells found in the neointimal lesion zone is also explained by proliferative changes.

Fibroblasts, endotheliocytes, myocytes of blood vessels, tumor cells are sensitive to the effects of everolimus on growth factor during proliferation.

In patients with renal cancer who underwent inhibition of the m-TOR protein with everolimus, death was prevented in 67 out of 100 cases, which is confirmed by the degree of significance using the Student's table.

The progress of diseases in these forms of cancer after the use of everolimus was absent for 5 months. More than a third of patients after taking everolimus, the progress of a cancerous tumor stopped for 6 months.

Instructions for use

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

Reception of a tablet should be completed with the use of a mill of cold purified water. It is not allowed to take a tablet with chewing, crushing and other violation of its integrity.

In case of physical impossibility for the patient to take the pill, it is placed in a glass cold water, dissolve it thoroughly and drink. After taking the everolimus solution, pour water into a glass and drink it, carrying away the remnants of the active substance and providing the desired concentration of the solution, suitable for absorption in the stomach.

The treatment regimen with everolimus is individual: the drug is stopped after the disappearance clinical symptoms or the appearance of a sign of poor tolerance to toxicity.

In most cases of cancer, the usual daily dose is 10 mg as a single dose. With the development of severe toxic reactions, the dosage of everolimus is reduced by 2 times or further use of the drug is canceled.

In patients with subependymal giant cell astrocytoma, the dosage is calculated starting at 4.5 mg/m 2 . The calculation of the body surface is carried out according to 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. At concentrations of everolimus below 3 ng / ml, the dosage of the drug is increased.

Side effects

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

Overdose

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

special instructions

Monitoring of the functioning of the kidneys during the period of treatment is carried out constantly. If a high concentration of daily creatinine in the patient's urine is detected, the treatment regimen is corrected, reducing the dosage of cyclosporine.

With daily monitoring of urinalysis, 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) are able to 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), protease inhibitors (amprenavir).

Afinitor: instructions for use and reviews

Structural formula

Russian name

Latin name of the substance Everolimus

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-tetraen-2,3,10,14,20-pentone

Gross formula

Pharmacological group of the substance Everolimus

CAS code

Use during pregnancy and lactation

Model clinical and pharmacological article 1

Pharma 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 their respective receptors. Blockade of the signal leads to the cessation of cell division at the G stage 1 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 the p70 S6 kinase is under the control of FRAP; the everolimus-FCBP-12 complex binds to FRAP. FRAP is a key regulatory protein that controls cellular metabolism, growth and proliferation; violation of its functions explains the arrest of the cell cycle caused by everolimus. Everolimus has a different mechanism of action than cyclosporine. The combination of everolimus with cyclosporine is more effective than either alone. Everolimus inhibits the proliferation of hematopoietic and non-hematopoietic cells (smooth muscle cells). 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 the dispersible tablets (compared to a conventional 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 - 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 blood concentration (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 blood concentration and plasma concentration is 17-73% (depending on the concentration values ​​in the range - 5-5000 ng / ml). When taking tablets with a very fatty meal, Cmax and AUC are reduced by 60% and 16%, respectively. Communication with proteins - 74%. Distribution volume - 235-449 l; volume of distribution (at steady state) - 110 l (deviation 36%). Everolimus is a substrate for 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. The total clearance is 8, l / h (deviation - 27%). T 1/2 - 21-35 hours Excreted by the intestines (80%) and kidneys (5%). In patients with hepatic insufficiency (class B on the Child-Puge scale), AUC increases by 2 times. The AUC index positively correlates with the concentration of bilirubin and an increase in prothrombin time and negatively with the concentration of serum albumin. In children from 1 to 16 years of age, clearance increases linearly depending on age, body surface area (0.49-1.92 sq.m), body weight (11-77 kg); in an equilibrium state, 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 in the equilibrium state is 2.7-6.1 ng / ml. In patients aged 16-70 years, there was a decrease in clearance of 0.3% per year. The total clearance in patients of the Negroid race is 20% higher. Everolimus basal concentration, acute rejection rate, and thrombocytopenia are associated (in kidney and heart transplant recipients within 6 months after transplantation). Everolimus exposure remains stable throughout the first year after transplantation. Pharmacokinetics in patients with kidney and heart transplants receiving everolimus 2 times a day simultaneously with cyclosporine (in the form of a microemulsion) is comparable.

Indications. Prevention of transplant 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 LF containing lactose (optional): hereditary galactose intolerance, lactase deficiency, glucose-galactose malabsorption.

Dosing. Inside, only with food or without it (for minimal variability), immediately after transplantation, simultaneously with cyclosporine (microemulsion); 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 dosing regimen is adjusted (based on the basal concentration of everolimus).

In liver failure (class A or B on the Child-Puge 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 more than 1.3 according to INR (increase more than 4 s). The dose is titrated based on therapeutic monitoring.

Blacks (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 often (more than 1/10), often (more than 1/100 and less than 1/10), infrequently (more than 1/1000 and less than 1/100), rarely (more than 1/10,000 and less than 1/1000) , very rare (less than 1/10000).

On the part of 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 side of the CCC: often - increased blood pressure, lymphocele (during kidney transplantation), phlebothrombosis.

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

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

From the side skin: often - angioedema (when taking ACE inhibitors), acne, complications from surgical wound; infrequently - rash.

From the musculoskeletal system: infrequently - myalgia.

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

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

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

Overdose. Treatment: symptomatic.

Interaction. It is metabolized with the participation of the CYP3A4 isoenzyme, is a substrate for the P-glycoprotein carrier protein, therefore, use with potent inhibitors or inducers of CYP3A4 is not recommended.

P-glycoprotein inhibitors can reduce the release of everolimus from intestinal cells and increase its serum concentration.

Everolimus is a competitive inhibitor of CYP3A4 and CYP2D6, potentially increasing the concentration of drugs metabolized with the participation of these enzymes. Caution should be exercised when co-administering everolimus with CYP3A4 substrates and CYP2D6 having a narrow therapeutic index.

The bioavailability of everolimus is significantly increased with the simultaneous use of cyclosporine (an inhibitor of CYP3A4 / P-glycoprotein).

Microemulsion cyclosporine increases everolimus AUC by 168% (46-365%) and Cmax by 82% (25-158%) compared with everolimus alone. When changing the dose of cyclosporine, a dose adjustment of everolimus may be required.

The clinical significance of the effect of everolimus on the pharmacokinetics of cyclosporine is minimal in kidney and heart transplant patients receiving cyclosporine in the form of a microemulsion.

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 (a CYP3A4 substrate) or pravastatin (a P-glycoprotein substrate) has no clinical effect on the pharmacokinetics of atorvastatin, pravastatin, everolimus, or on the total bioreactivity of HMG-CoA reductase in plasma. However, these results do not take into account the effect of other inhibitors of HMG-CoA reductase. Patients receiving HMG-CoA reductase inhibitors should be observed for the development of rhabdomyolysis and other adverse events.

Moderate inhibitors of CYP3A4 and P-glycoprotein (fluconazole, erythromycin, verapamil, nicardipine, diltiazem, nelfinavir, indinavir, amprenavir) can increase the concentration of everolimus in the blood.

CYP3A4 inducers (St. John's wort, carbamazepine, phenobarbital, phenytoin, efavirenz, nevirapine) may increase the metabolism of everolimus and decrease its blood levels.

Grapefruit juice affects the activity of cytochrome P450 and P-glycoprotein, so its simultaneous use with everolimus should be avoided.

During treatment with everolimus, vaccination may be less effective. The use of live vaccines should be avoided.

Special instructions. Treatment should only be administered by clinicians experienced in immunosuppressive therapy after organ transplantation and able to monitor whole blood concentrations of everolimus.

In patients with a basal concentration of 3 ng / ml or more, the frequency of acute rejection (kidneys and hearts) is lower than in patients with a basal concentration of less than 3 ng / ml.

In patients with hepatic insufficiency, with the simultaneous use of potent inducers and inhibitors of CYP3A4, when switching to other LF and / or if the dose of cyclosporine is significantly reduced, it is necessary to control the concentration of everolimus in the blood.

Everolimus concentrations are somewhat lower with dispersible tablets 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. Dose reduction of ciclosporin is initiated 1 month after renal transplantation, resulting in an improvement in renal function.

The 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.

very important (in early period after transplantation) to ensure that everolimus and ciclosporin concentrations do not fall below the therapeutic range to minimize the risk of failure. Before reducing the dose of cyclosporine, it should be clarified that the equilibrium concentration of everolimus is 3 ng / ml or more.

There are limited data on the use of everolimus when basal ciclosporin levels are less than 50 ng/ml or maintenance phase ciclosporin levels are less than 350 ng/ml.

If the patient cannot tolerate a reduction in the dose of ciclosporin, then the subsequent use of everolimus should be reconsidered.

In maintenance phase heart transplant patients, the dose of ciclosporin should be reduced to improve renal function.

If renal function worsens or if CC is less than 60 ml / min, a correction of the therapy regimen is necessary. The dose of cyclosporine is set on the basis of its basal concentration.

In heart transplantation, there are limited data on the use of everolimus with a basal ciclosporin concentration of less than 175 ng/ml in the first 3 months; less than 135 ng/ml — for 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 corticosteroids.

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

It is necessary to control the concentration of everolimus in the blood while using with inducers or inhibitors of CYP3A4 and after their cancellation.

During the period of treatment, the condition of patients should be monitored to detect skin neoplasms; exposure to UV radiation should be minimized, sunlight, use appropriate sunscreen. The risk of skin neoplasms is associated more with the duration and intensity of immunosuppression than with the use of a particular drug. Excessive immunosuppression predisposes to the development of infections, especially opportunistic ones. There are reports of fatal infections and sepsis.

The combined use of everolimus with cyclosporine (microemulsion) increases serum cholesterol and triglycerides, which may require appropriate treatment. Patients should be monitored for hyperlipidemia, treated with lipid-lowering drugs if necessary, and given an appropriate diet.

In case of detection of hyperlipidemia in the appointment of immunosuppressive drugs, it is necessary to evaluate 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 observed for the development of adverse events caused by the above drugs.

Caution should be exercised while using other drugs that have a negative effect on kidney function. There are limited data on the use of everolimus in children undergoing kidney transplantation.

In patients with hepatic insufficiency, the basal concentration of everolimus in whole blood should be carefully monitored.

State register of medicines. Official publication: in 2 volumes - M .: Medical Council, 2009. - V.2, part 1 - 568 p.; part 2 - 560 p.

L04AA18 (Everolimus)
L01XE10 (Everolimus)

You should consult with your doctor before using EVEROLIMUS. These instructions for use are for informational purposes only. For more information, please refer to the manufacturer's annotation.

Clinical and pharmacological groups

14.015 (Immunosuppressive drug)
22.011 (Antineoplastic drug. Protein tyrosine kinase inhibitor)

pharmachologic effect

Immunosuppressant, proliferative signal inhibitor. 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 results in cell proliferation driven by the binding of these T cell growth factors to their respective receptors. Blockade of this signal by everolimus leads to the arrest of cell division at the G1 stage of the cell cycle.

At the molecular level, everolimus forms a complex with the cytoplasmic protein FKBP-12. In the presence of everolimus, phosphorylation of p70 S6 kinase stimulated by growth factor is inhibited. Since p70 S6 kinase phosphorylation is under the control of FRAP (so-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; the disruption of FRAP function thus explains the cell cycle arrest induced by everolimus. Everolimus thus has a different mechanism of action than cyclosporine. In preclinical allotransplantation models, the combination of everolimus with has been shown to be more effective than with either alone.

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.

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

Pharmacokinetics

After oral administration, Cmax is reached after 1-2 hours. In patients after transplantation, the concentration of everolimus in the blood is proportional to the dose in the dose range from 0.25 mg to 15 mg.

The ratio of the concentration of everolimus in the blood and its concentration in plasma is in the range from 17% to 73% and depends on the concentration values ​​in the range from 5 to 5000 ng / ml. In healthy volunteers and patients with moderate hepatic impairment, plasma protein binding is approximately 74%. Vd in the final phase in patients after kidney transplantation who are on maintenance therapy is 342 ± 107 liters.

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

After administration of a single dose of radiolabelled everolimus to transplant patients receiving cyclosporine, most (80%) of the radioactivity was determined in the feces, a small amount (5%) was excreted in the urine. The unchanged substance was not determined either in the urine or in the feces.

In patients with moderately severe hepatic impairment (Child-Pugh class B), the AUC of everolimus increased. AUC was positively correlated with serum bilirubin concentration and prolongation of prothrombin time 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

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). In the equilibrium state, the 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 the basal concentration of everolimus and the frequency of biopsy-proven acute rejection and thrombocytopenia.

Kidney transplantationC0 (ng/ml)
≤3.4
3.5-4.5
4.6-5.7
5.8-7.7
7.8-15
No rejection
68%
81%
86%
81%
91%
Thrombocytopenia (10%
9%
7%
14%
17%
Heart transplantationC0 (ng/ml)
≤3,5
3.6-5.3
5.4-7.3
7.4-10.2
10.3-21.8
No rejection
65%
69%
80%
85%
85%
Thrombocytopenia (5%
5%
6%
8%
9%

EVEROLIMUS: DOSAGE

Taken inside.

The recommended initial dose of the drug for adult patients with kidney and heart transplants is 0.75 mg 2 times / day. Application should begin as soon as possible after transplantation. The daily dose is divided into 2 doses and taken either always with food, or always without it. Taken at the same time with cyclosporine in a special dosage form. It may be necessary to adjust the dosing regimen of everolimus, taking into account the achieved plasma concentrations, tolerability, individual response to treatment, changes in concomitant drug therapy and clinical situation. Correction of the dosing regimen can be carried out at intervals of 4-5 days.

The incidence of biopsy-proven acute rejection was higher in blacks than in non-blacks.

In patients with hepatic insufficiency, the basal concentration of everolimus in whole blood should be carefully monitored. In patients with mild to moderate hepatic insufficiency (Child-Pugh class A or B), the dose should be reduced to approximately 2 times the mean dose when there is a combination of two of the following: bilirubin >34 µmol/l (> 2 mg/dl), albumin 1.3 INR (prolongation >4 sec). Further dose titration is carried out under the control of the concentration of everolimus in the blood plasma.

drug interaction

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

The bioavailability of everolimus was significantly increased with the simultaneous use of cyclosporine (an inhibitor of CYP3A4 / P-glycoprotein).

When studying drug interaction in healthy volunteers who had previously received multiple doses of rifampicin (an inducer of CYP3A4), subsequent use of everolimus in a single dose showed an almost 3-fold increase in everolimus clearance and a decrease in Cmax by 58% and AUC by 63% (this combination is not recommended).

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

CYP3A4 inducers can increase the metabolism of everolimus and reduce the concentration of everolimus in the blood, 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 and P-glycoprotein isoenzymes, so these juices should be avoided while taking everolimus.

Since immunosuppressants may interfere with the response to vaccination, vaccination may be less effective during treatment with everolimus.

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 secreted from breast milk in a person. If it is necessary to use everolimus during lactation, the issue of stopping breastfeeding should be considered.

Experimental studies have shown the presence of toxic effects on reproduction, including embryotoxicity and fetotoxicity. It is not known if there is a potential risk to humans. It has been shown that everolimus and/or its metabolites rapidly penetrate into the milk of lactating rats.

EVEROLIMUS: SIDE EFFECTS

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

From the side endocrine system: sometimes - hypogonadism in men (decrease in testosterone levels, increase in LH levels).

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

From the side of cardio-vascular 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, ACT, 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.

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

In controlled clinical trials 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 using everolimus with other immunosuppressants; malignant neoplasms skin (1.3%); other types of malignancy (1.2%).

Indications

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

Contraindications

Hypersensitivity to everolimus, sirolimus.

special instructions

During the period of treatment, regular monitoring of kidney function is recommended. With an increase in serum creatinine, consideration should be given to adjusting the immunosuppressive therapy regimen, in particular, reducing the dose of cyclosporine. Others should be used with caution medicines which can impair kidney function.

Co-administration with strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir) and inducers (eg, rifampicin, rifabutin) is not recommended unless the expected benefit of such therapy outweighs the potential risk. It is recommended to monitor the concentration of everolimus in whole blood with simultaneous use with inducers or inhibitors of CYP3A4 and after their withdrawal.

Everolimus has not been studied in patients with severe hepatic impairment. It is recommended that everolimus plasma concentrations be carefully monitored in patients with hepatic impairment.

Patients receiving immunosuppressant therapy, including everolimus, have an increased risk of developing lymphomas and other malignancies, especially of the skin. Patients should be regularly monitored for skin lesions, advised to minimize exposure to ultraviolet radiation, sunlight, and use appropriate sunscreen.

Use with caution in patients with hyperlipidemia. During the period of treatment, the content of cholesterol and triglycerides in the blood should be monitored.

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 in order to timely detect rhabdomyolysis.

Live vaccines should not be used during treatment with everolimus.

In 1 tablet everolimus 5 or 10 mg. Crospovidone, lactose, hypromellose, lactose monohydrate, butylhydroxytoluene, magnesium stearate, as excipients.

Release form

Tablets 2.5; 5 and 10 mg.

Soluble tablets 2.3 and 5 mg.

pharmachologic effect

Antitumor.

Pharmacodynamics and pharmacokinetics

Pharmacodynamics

An anticancer drug that is an inhibitor mTOR kinases and specifically affects the complex mTORC1 , which is a regulator of protein synthesis, controls cell growth and proliferation. Inhibition of its activity is accompanied by a loss of the ability to transmit signals and stop the cell cycle. This inhibits the proliferation of not only tumor cells, but blood vessels. As a result, tumor growth stops. In patients with progressive renal cell carcinoma the drug reduced the risk of progression by 67% and increased life expectancy. In 36%, there was no progression of the disease within six months. Application everolimus significantly improves the quality of life of patients.

Pharmacokinetics

When taken orally Cmax in the blood is determined after 1-2 hours. When taken with fatty foods, it decreases Cmax by 54%. Protein binding 74%. The equilibrium state is reached in 2 weeks of daily intake. T1/2 is 30 hours. It circulates in the blood unchanged and in the form of 6 main metabolites, which are 100 times less active. Metabolites are excreted mainly in feces and urine. In patients with mild liver dysfunction, the value AUC 2 times more than in normal liver function. There was no significant effect of the age of patients on the clearance of the active substance.

Indications for use

• neuroendocrine tumors lung gastrointestinal tract and pancreas;
• renal cell carcinoma (in case of failure antiangiogenic therapy );
• hormone-dependent in postmenopausal women (combination therapy with an inhibitor aromatase );
• subependymal astrocytomas in children older than 3 years;
• and tuberous sclerosis .

Contraindications

• hypersensitivity;
• lactation;
• age up to 18 years;
• simultaneous use with CYP3A4 inducers .

Prescribed with caution before surgical interventions as it slows down wound healing. As well as patients with hereditary intolerance galactose and lactase deficiency . During treatment and within 2 months after the end of treatment, contraceptives must be used.

Side effects

Common side reactions:

• lymphocytopenia , thrombocytopenia , anemia ;
• conjunctivitis , swelling of the eyelids;
• , cough, hemoptysis, epistaxis;
• lack of appetite, vomiting, abdominal pain, dry mouth;
• rash, itching,;
• exacerbation;
• increase in blood triglycerides , creatinine ;
• dehydration, weight loss;
• anaphylactic reactions , difficulty breathing;
• asthenia , increased fatigue;
• edema exacerbation of secondary infections.

Afinitor, instructions for use (Method and dosage)

Tablets are taken orally 1 time per day, preferably in the morning, on an empty stomach. Tablets are swallowed whole, without crushing, washing down with a large amount of liquid. Treatment lasts as long as there is a clinical effect. Afinitor 10 mg is usually prescribed, and in severe adverse reactions, reduce the dose to 5 mg.

When used with CYP3A4 inducers the dose is gradually increased to 20 mg, and when therapy is stopped, they return to the initial dose. For the elderly, dose adjustment is not carried out. Also, it is not carried out in violation of kidney function. The dose is reduced to 5 mg in patients with impaired liver function.

Overdose

Cases of overdose are not known. Even with a single dose of up to 70 mg, tolerability is satisfactory. In case of overdose, symptomatic treatment is prescribed.

Interaction

The absorption and excretion of the active substance is affected by drugs that interact with CYP3A4 and P-glycoprotein . Concentration everolimus increased when used with inhibitors isoenzyme CYP3A4 or P-glycoprotein . In this connection, the simultaneous administration of strong inhibitors of the isoenzyme should be avoided: posaconazole , clarithromycin , ritonavir , nephazodon , saquinavir , atazanavir , indinavir .

Bioavailability everolimus increased when combined with. Caution should be used with moderate inhibitors isoenzyme : ,