Everolimus Immunosuppressive remedy, inhibitors of a proliferative signal. A derivative of sirolimus; inhibits the proliferation of antigen-activated t cells and, therefore, clonal expansion, caused by specific t-cell interleukins, such as interleukin 2 and interleukin 15. It also inhibits the intracellular signaling pathway, which usually leads to cell proliferation, provoked by binding these cell growth factors with appropriate receptors. The blockade of this signal leads to the stop of cell division in the 1st stage of the cell cycle.
After oral administration, the maximum concentration is reached in 1-2 hours. When taking the drug with fatty foods, the maximum concentration and effect are reduced by 60 and 16%, respectively. Connection with plasma proteins is ~ 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 involving CYP34 and P-glycoprotein, to two major inactive metabolites. In systemic blood flow mostly Everolimus. Elimination with feces (80% as metabolites), urine (5% as metabolites). Time to reach maximum concentration is 1-2 hours. When administered orally at doses of 0.75 mg and 1.5 mg twice a day, the maximum concentration is 11.1 ± 4.6 and 20.3 ± 8.0 mg/ml, respectively. Exposure system 75 ± 31 and 131 ± 59 mg × h/ml, respectively. Creatinine clearance 8.8 l / h (range – 27%). The half-life is 28 ± 7 hours.
Prevention of rejection of kidney and heart transplant in adult recipients with low and medium immunological risk receiving basic immunosuppressive therapy (cyclosporine and glucocorticosteroids).
Common and/or metastatic renal cell carcinoma (with the inefficiency of anti-angiogenic therapy).
Hypersensitivity, children’s age.
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 is excreted in human milk. If it is necessary to use everolimus during lactation, the question of stopping breastfeeding should be resolved.
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. It was 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).
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.
From the hemopoietic system and the lymphatic system: very often – leukopenia; often – thrombocytopenia, anemia, coagulopathy, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome; sometimes hemolysis.
On the part of the endocrine system: sometimes – hypogonadism in men (lower testosterone levels, increased levels of LH).
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 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 – edema, 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%).
In experimental studies, it has been 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.