Everolimus - instructions for use, doses, side effects, contraindications

Immunosuppressive agent, inhibitor of the proliferative signal. The sirolimus derivative; inhibits antigen-activated T cell proliferation and, accordingly, clonal expansion caused by specific T-cell interleukins, for example interleukin 2 and interleukin 15. Also inhibits the intracellular signaling pathway that normally leads to cell proliferation triggered by the binding of these T cell growth factors to corresponding receptors. The blockade of this signal leads to a stop of cell division in the G stage₁ cell cycle.

Pharmacokinetics:

After oral administration, the maximum concentrationis achieved after 1-2 hours. When taking the drug with a very fatty food, the maximum concentration and systemic exposureare reduced by 60 and 16% respectively. Relationship with plasma proteins ~ 74%.The volume of distribution is 5.31 ± 1.52 l / kg. Biotransformation: mainly in the liver, to some extent - in the intestinal wall by monohydroxylation and O-dealkylation with the participation of CYP34 and P-glycoprotein, up to two major inactive metabolites. In the systemic circulation is mainly everolimus. Elimination with feces (80% in the form of metabolites), urine (5% in the form of metabolites). The time to reach the maximum concentration1-2 hours. When administered orally at doses of 0.75 mg and 1.5 mg twice daily, the maximum concentration is 11.1 ± 4.6 and 20.3 ± 8.0 ng / ml, respectively. The system exposure is 75 ± 31 and 131 ± 59 ng × h / ml, respectively. Creatinine clearance 8.8 l / h (range - 27%). Half-life28 ± 7 hours.

Indications:

Prevention of rejection of kidney and heart transplant in adult recipients with low and medium immunological risk receiving basic immunosuppressive therapy (ciclosporin and glucocorticosteroids).

Common and / or metastatic renal cell carcinoma (with inefficiency of anti-angiogenic therapy).

ICD-10

XXI.Z80-Z99.Z94.1 Presence of a transplanted heart

XXI.Z80-Z99.Z94.0 Presence of a transplanted kidney

XXI.Z80-Z99.Z94 Presence of transplanted organs and tissues

XIX.T80-T88.T86.2 Dying and rejection of heart transplant

XIX.T80-T88.T86.1 Dying and rejection of a kidney transplant

Contraindications:

Hypersensitivity, children's age.

Carefully:

Hepatic failure, chronic renal failure, pregnancy. For medicinal forms containing lactose (in addition): hereditary intolerance to galactose, lactase deficiency, glucose-galactose malabsorption.

Pregnancy and lactation:

There are no data on pregnancy use. Do not use everolimus during pregnancy, except when the expected benefit to the mother exceeds the potential risk to the fetus.

Women of childbearing age should be recommended to use effective methods of contraception during the treatment period and within 8 weeks after the end of therapy.

It is not known whether everolimus with human breast milk. If it is necessary to use everolimus during lactation, the question of stopping breastfeeding should be solved.

In experimental studies, the presence of toxic effects on reproductive performance, including embryotoxicity and fetotoxicity, has been shown. It is not known whether there is a potential risk to humans.Shown, that everolimus and / or its metabolites quickly penetrated the milk of lactating rats.

Dosing and Administration:

Inside only with food or without it (for minimal variability) immediately after transplantation, simultaneously with cyclosporine (microemulsion); the tablets are swallowed whole, with a glass of water (or in the form of dispersible tablets) 0.5 mg twice 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-Pug scale), the dose is reduced by a factor of 2 (compared with 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 by INR (increase more than 4 s). The dose is titrated based on therapeutic monitoring.

Representatives of the Negroid race (for limited information) may need a higher dose to achieve the same effect as other patients receiving the drug in the recommended adult dose.

Side effects:

From the side system of hematopoiesis 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 level, increase in LH level).

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

From the side of cardio-vascular system: often - increased blood pressure, lymphocele, venous thrombosis.

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

From the side digestive system: often - abdominal pain, diarrhea, nausea, vomiting; sometimes - hepatitis, violations of the liver, jaundice, increased ALT, ACT, GGT.

From the side skin and subcutaneous tissue: often - angioedema, acne, complications from the surgical wound; sometimes - a rash.

From the side musculoskeletal system: sometimes - myalgia.

From the side 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 observed for at least one year, lymphoma or lymphoproliferative disease was reported in 1.4% of cases with the use of everolimus with other immunosuppressants; malignant neoplasms of the skin (1.3%); other types of malignancy (1.2%).

Overdose:

In experimental studies it was shown that everolimus has a low acute toxicity potential. After oral administration of the drug at a dose of 2000 mg / kg, no single deaths or severe toxicity were observed in mice and rats (control over the range of values). Reports of cases of overdose in humans are very limited. There is only one fact of a random intake of 1.5 mg everolimus by a child at the age of 2 years, with no adverse events observed. At a single oral intake in doses up to 25 mg in patients after transplantation, acceptable tolerability of the drug was noted.

Treatment: symptomatic.

Interaction:

Metabolized with the participation of the CYP3A4 isoenzyme, is a substrate for the P-glycoprotein carrier protein, hence, the 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 concentration in serum.

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

Bioavailability of everolimus significantly increases with the simultaneous use of cyclosporine (inhibitor of CYP3A4 / P-glycoprotein).

Ciclosporin in the form of a microemulsion increases the systemic exposure of everolimus by 168% (46-365%) and maximum concentration by 82% (25-158%) compared with the use of only one everolimus. When changing the dose of cyclosporine, you may need to adjust the dose of everolimus.

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

The use of everolimus after multiple doses of rifampicin (inducer CYP3A4), increases the clearance of everolimus 3-fold, reduces the maximum concentration by 58% and systemic exposure by 63%.

The combined use of everolimus with rifampicin is not recommended.

The administration of a single dose of everolimus with atorvastatin (substrate CYP3A4) or pravastatin (substrate P-glycoprotein) does not have a clinical effect on the pharmacokinetics of atorvastatin, pravastatin, everolimus, and the overall bioreactivity of HMG-CoA reductase in plasma. However, these results do not take into account the effect of other HMG-CoA reductase inhibitors. Patients receiving inhibitors of HMG-CoA reductase should be monitored for rhabdomyolysis and other undesirable 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.

Inductors CYP3A4 (St. John's Wort, carbamazepine, phenobarbital, phenytoin, efavirenz, nevirapine) can increase the metabolism of everolimus and reduce its concentration in the blood.

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

Against the background of treatment with everolimus, vaccination may be less effective.Use of live vaccines should be avoided.

Special instructions:

Treatment should be performed only by physicians with experience of immunosuppressive therapy after organ transplantation, and the ability to monitor the concentration of everolimus in whole blood.

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

The recommended upper limit of the therapeutic concentration of everolimus is 8 ng / ml.

In patients with hepatic insufficiency, while using powerful inducers and inhibitors of CYP3A4, when switching to other dosage forms and / or if the dose of cyclosporine is significantly reduced, it is necessary to monitor the concentration of everolimus in the blood.

The concentrations of everolimus when using dispersible tablets are somewhat lower than with conventional tablets.

Because the ciclosporin 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 for a long time with cyclosporine in a full dose.A decrease in the dose of cyclosporine begins 1 month after renal transplantation, which leads to an improvement in kidney function.

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

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

There are limited data on the use of everolimus with a basal cyclosporin concentration of less than 50 ng / ml or a cyclosporin concentration in the maintenance phase of less than 350 ng / ml.

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

In patients after heart transplantation in the supporting phase, a dose of cyclosporin should be reduced to improve kidney function.

If the kidney function worsens, or if the creatinine clearance is less than 60 ml / min, correction of the therapy regimen is necessary.The dose of cyclosporine is established based on its basal concentration.

In heart transplantation, there are limited data on the use of everolimus with a basal cyclosporin 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 concomitantly with cyclosporine in the form of a microemulsion, basiliximab and glucocorticosteroids.

It is not recommended to use together with powerful inhibitors of CYP3A4 (ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir) and inductors (rifampicin, rifabutin), except when the expected benefit of therapy exceeds the potential risk.

It is necessary to monitor the concentrations of everolimus in the blood with simultaneous use with inducers or inhibitors of CYP3A4 and after their cancellation.

During the treatment period, patients should be monitored to detect skin lesions; it is necessary to minimize the impact of UV radiation, sunlight, use appropriate sunscreen. The risk of skin lesions is associated 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 infections. There are reports of the development of fatal infections and sepsis.

Within 3 months after transplantation, it is recommended to prophylaxis of cytomegalovirus infection (in patients with an increased risk of infection).

The combined use of everolimus with cyclosporine (microemulsion) increases serum cholesterol and TG, which may require appropriate treatment. Patients should be observed to identify hyperlipidemia, if necessary, to treat lipid-lowering medications and prescribe the appropriate diet.

In case of detection of hyperlipidemia in the appointment of immunosuppressive drugs, it is necessary to assess the risk / benefit ratio.

The risk / benefit ratio of everolimus therapy should be evaluated in patients with severe reflux hyperlipidemia. Patients receiving HMG-CoA reductase inhibitors and / or fibrates should be monitored for adverse events caused by the above drugs.

During the treatment, all patients are recommended control of kidney function.With an increase in creatinine clearance, the question of correction of immunosuppressive therapy (reduction of the dose of cyclosporine) should be addressed.

Care should be taken when using other drugs that have a negative effect on kidney function. There are limited data on the use of everolimus in children with kidney transplantation.

Patients with hepatic insufficiency should carefully monitor the basal concentration of everolimus in whole blood.

Women of childbearing age should be recommended to use effective methods of contraception during the treatment period and within 8 weeks after the end of therapy.

Instructions

Everolimus (Everolimusum)