Everolimus-Amedart (Tablets) Instructions for Use

Marketing Authorization Holder

Amedart LLC (Russia)

ATC Code

L04AA18 (Everolimus)

Active Substance

Everolimus (Rec.INN registered by WHO)

Dosage Forms

	Everolimus-Amedart	Tablets 0.5 mg: 50, 60, 100 or 250 pcs.
		Tablets 0.25 mg: 50, 60, 100 or 250 pcs.
		Tablets 0.75 mg: 50, 60, 100 or 250 pcs.
		Tablets 1 mg: 50, 60, 100 or 250 pcs.

Dosage Form, Packaging, and Composition

Tablets are round, biconvex, from white to white with a yellowish tint; marbling is allowed.

Excipients: butylhydroxytoluene, lactose monohydrate, hypromellose, crospovidone, magnesium stearate, anhydrous lactose.

50 pcs. – high-density polyethylene jars (1) – cardboard packs with an insert.
60 pcs. – high-density polyethylene jars (1) – cardboard packs with an insert.
100 pcs. – high-density polyethylene jars (1) – cardboard packs with an insert.
250 pcs. – high-density polyethylene jars (1) – cardboard packs with an insert.

Tablets are round, biconvex, from white to white with a yellowish tint; marbling is allowed.

Excipients: butylhydroxytoluene, lactose monohydrate, hypromellose, crospovidone, magnesium stearate, anhydrous lactose.

50 pcs. – high-density polyethylene jars (1) – cardboard packs with an insert.
60 pcs. – high-density polyethylene jars (1) – cardboard packs with an insert.
100 pcs. – high-density polyethylene jars (1) – cardboard packs with an insert.
250 pcs. – high-density polyethylene jars (1) – cardboard packs with an insert.

Tablets are round, biconvex, from white to white with a yellowish tint; marbling is allowed.

Excipients: butylhydroxytoluene, lactose monohydrate, hypromellose, crospovidone, magnesium stearate, anhydrous lactose.

50 pcs. – high-density polyethylene jars (1) – cardboard packs with an insert.
60 pcs. – high-density polyethylene jars (1) – cardboard packs with an insert.
100 pcs. – high-density polyethylene jars (1) – cardboard packs with an insert.
250 pcs. – high-density polyethylene jars (1) – cardboard packs with an insert.

Tablets are round, biconvex, from white to white with a yellowish tint; marbling is allowed.

Excipients: butylhydroxytoluene, lactose monohydrate, hypromellose, crospovidone, magnesium stearate, anhydrous lactose.

50 pcs. – high-density polyethylene jars (1) – cardboard packs with an insert.
60 pcs. – high-density polyethylene jars (1) – cardboard packs with an insert.
100 pcs. – high-density polyethylene jars (1) – cardboard packs with an insert.
250 pcs. – high-density polyethylene jars (1) – cardboard packs with an insert.

Clinical-Pharmacological Group

Immunosuppressive drug

Pharmacotherapeutic Group

Immunosuppressants, selective immunosuppressants

Pharmacological Action

Everolimus is an immunosuppressant, a signal transduction inhibitor. Its immunosuppressive effect is due to the inhibition of antigen-activated proliferation of T-cells 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 respective receptors. The blockade of this signal by everolimus results in the arrest of cell division in the G₁ phase of the cell cycle.

At the molecular level, Everolimus forms a complex with the cytoplasmic protein FKBP-12. In the presence of everolimus, the phosphorylation of p70 S6 kinase stimulated by growth factor is inhibited. Since the phosphorylation of p70 S6 kinase is controlled by FRAP (so-called mTOR), these data suggest that the Everolimus-FKBP-12 complex binds to FRAP.

FRAP is a key regulatory protein that controls cell metabolism, growth, and proliferation; disruption of FRAP function thus explains the cell cycle arrest caused by everolimus. Everolimus therefore has a mechanism of action different from cyclosporine. In preclinical models of allotransplantation, the combination of everolimus with cyclosporine was shown to be more effective than the isolated use of each.

In addition to its effect on T-cells, Everolimus inhibits growth factor-stimulated proliferation of both hematopoietic and non-hematopoietic cells (e.g., smooth muscle cells). Growth factor-stimulated proliferation of vascular smooth muscle cells, which is triggered by endothelial cell damage and leads to neointima formation, 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 vascular smooth muscle cells.

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 patient death by 67%. When using everolimus, the progression-free survival of patients was 4.9 months. Within 6 months, 36% of patients receiving Everolimus had no disease progression. It is believed that the use of everolimus can significantly improve the quality of life of patients (the impact of disease symptoms on various areas of the patient’s life was assessed).

Pharmacokinetics

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

The ratio of everolimus concentration in blood to its concentration in plasma ranges from 17% to 73% and depends on 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%. The V_d in the terminal phase in kidney transplant patients 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 main metabolites are formed by hydrolysis of the cyclic lactone. None of them have significant immunosuppressive activity. Everolimus itself is mainly found in the systemic circulation.

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

In patients with moderate hepatic impairment (Child-Pugh class B), the AUC of everolimus increased. The AUC indicator positively correlated with serum bilirubin concentration and increased prothrombin time and negatively correlated with serum albumin concentration. If the bilirubin concentration was > 34 µmol/L, prothrombin time >1.3 INR (prolongation > 4 sec) and/or albumin concentration was < 35 g/L, then there was a tendency for an increase in AUC in patients with moderate hepatic insufficiency. In severe hepatic insufficiency (Child-Pugh class C), changes in AUC have not been studied, but they are likely to be the same or more pronounced than in moderate hepatic insufficiency.

The clearance of everolimus 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, T_1/2 was 30±11 hours.

In kidney and heart recipients within 6 months after transplantation, an association was found between the baseline concentration of everolimus and the incidence of biopsy-confirmed acute rejection and thrombocytopenia.

Indications

Prophylaxis of rejection of kidney and heart transplants in adult recipients with low and moderate immunological risk receiving basic immunosuppressive therapy with cyclosporine and corticosteroids. Prophylaxis of liver transplant rejection in recipients with low and moderate immunological risk receiving basic immunosuppressive therapy with tacrolimus and corticosteroids.

ICD codes

Dosage Regimen

Take orally.

As a means of prophylaxis of transplant rejection, the recommended initial dose for adults with kidney and heart transplants is 750 mcg twice daily. Use should be started as soon as possible after transplantation. It is taken at the same time as cyclosporine in a special dosage form. Adjustment of the everolimus dosing regimen may be required based on achieved plasma concentrations, tolerability, individual treatment response, changes in concomitant drug therapy, and the clinical situation. Dosing regimen adjustments can be made at intervals of 4-5 days.

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

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

Adverse Reactions

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 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, surgical wound complications; sometimes – rash.

From the musculoskeletal system: sometimes – myalgia.

From the urinary system: often – urinary tract infections; sometimes – renal tubular necrosis, pyelonephritis.

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

In controlled clinical trials where patients were observed 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; skin malignancies (1.3%); other types of malignancy (1.2%).

Contraindications

Hypersensitivity to everolimus, sirolimus.

Use in Pregnancy and Lactation

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

Women of childbearing potential should be advised to use effective methods of contraception during treatment and for 8 weeks after the end of therapy.

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

In experimental studies, toxic effects on reproduction, including embryotoxicity and fetotoxicity, have been shown. It is not known whether there is a potential risk to humans. Everolimus and/or its metabolites have been shown to rapidly penetrate into the milk of lactating rats.

Special Precautions

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. Other drugs that may impair renal function should be used with caution concomitantly.

Concomitant use with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir) and inducers (e.g., rifampicin, rifabutin) is not recommended, except in cases where the expected benefit of such therapy outweighs the potential risk. Monitoring of everolimus concentrations in whole blood is recommended when used concomitantly with CYP3A4 inducers or inhibitors and after their withdrawal.

Everolimus has not been studied in patients with severe hepatic impairment. Careful monitoring of everolimus plasma concentrations is recommended in patients with hepatic impairment.

During treatment, patients should be monitored for the detection of skin neoplasms. Patients should be regularly monitored for the detection of skin neoplasms, advised to minimize exposure to ultraviolet radiation, sunlight and to use appropriate sun protection.

Use with caution in patients with hyperlipidemia. During treatment, blood cholesterol and triglyceride levels should be monitored. The risk/benefit ratio of continuing everolimus therapy should be assessed in patients with severe refractory hyperlipidemia. 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 have been reports of fatal infections and sepsis.

Within 3 months after transplantation, prophylaxis for cytomegalovirus infection is recommended, especially in patients at increased risk of its development.

Patients receiving HMG-CoA reductase inhibitors require clinical monitoring for the timely detection of rhabdomyolysis.

Live vaccines should not be used during treatment with everolimus.

Drug Interactions

The absorption and subsequent elimination of everolimus can be affected by drugs that interact with CYP3A4 and/or P-glycoprotein. Concomitant use of everolimus with strong inhibitors or inducers of CYP3A4 is not recommended. P-glycoprotein inhibitors may 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 eliminated by these enzymes.

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

In a drug interaction study in healthy volunteers who received prior therapy with multiple doses of rifampicin (CYP3A4 inducer), subsequent use of a single dose of everolimus resulted in an almost 3-fold increase in everolimus clearance and a decrease in C_max by 58% and AUC by 63% (this combination is not recommended).

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

CYP3A4 inducers may increase the metabolism of everolimus and decrease everolimus blood concentrations, including St. John’s wort, anticonvulsants ( carbamazepine, phenobarbital, phenytoin); HIV treatment drugs ( efavirenz, nevirapine).

Grapefruit and grapefruit juice affect the activity of CYP isoenzymes and P-glycoprotein, therefore consumption of these juices should be avoided during everolimus therapy.

Since immunosuppressants can affect the vaccination response, vaccination during treatment with everolimus may be less effective.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.