Roliveka^® (Tablets) Instructions for Use

Marketing Authorization Holder

Izvarino Pharma LLC (Russia)

Manufactured By

Nanopharma Development, LLC (Russia)

ATC Code

L04AA18 (Everolimus)

Active Substance

Everolimus (Rec.INN WHO registered)

Dosage Forms

	Roliveka^®	Tablets 0.5 mg
		Tablets 0.25 mg
		Tablets 0.75 mg
		Tablets 1 mg

Dosage Form, Packaging, and Composition

Tablets

	1 tab.
Everolimus	0.5 mg

10 pcs. – blister packs (10 pcs.) – cardboard packs (100 pcs.) – By prescription
10 pcs. – blister packs (150 pcs.) – cardboard boxes (1500 pcs.) – In-Bulk
10 pcs. – blister packs (200 pcs.) – cardboard boxes (2000 pcs.) – In-Bulk
10 pcs. – blister packs (25 pcs.) – cardboard packs (250 pcs.) – By prescription
10 pcs. – blister packs (3 pcs.) – cardboard packs (30 pcs.) – By prescription
10 pcs. – blister packs (300 pcs.) – cardboard boxes (3000 pcs.) – In-Bulk
10 pcs. – blister packs (400 pcs.) – cardboard boxes (4000 pcs.) – In-Bulk
10 pcs. – blister packs (5 pcs.) – cardboard packs (50 pcs.) – By prescription
10 pcs. – blister packs (500 pcs.) – cardboard boxes (5000 pcs.) – In-Bulk
10 pcs. – blister packs (6 pcs.) – cardboard packs (60 pcs.) – By prescription
10 pcs. – blister packs (600 pcs.) – cardboard boxes (6000 pcs.) – In-Bulk

Tablets

	1 tab.
Everolimus	0.25 mg

Tablets

	1 tab.
Everolimus	0.75 mg

Tablets

	1 tab.
Everolimus	1 mg

Clinical-Pharmacological Group

Immunosuppressive drug

Pharmacotherapeutic Group

Immunosuppressants, selective immunosuppressants

Pharmacological Action

Everolimus is an immunosuppressant, an inhibitor of proliferative signal transduction.

The immunosuppressive effect is due to the inhibition of antigen-activated proliferation of T-cells 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 leads to the arrest of cell division at 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, growth factor-stimulated phosphorylation of p70 S6 kinase is inhibited.

Since the phosphorylation of p70 S6 kinase is under the control of FRAP (so-called m-TOR), 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 thus 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 of them.

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 the concentration of everolimus in blood to its concentration in plasma ranges 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, binding to plasma proteins 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 has significant immunosuppressive activity.

Everolimus 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 found in the feces, and a small amount (5%) was excreted in the urine.

No unchanged substance was found 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 to increase the AUC indicator 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 the patient’s 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, a relationship was found between the baseline concentration of everolimus and the incidence of biopsy-confirmed acute rejection and thrombocytopenia.

Kidney Transplantation
C₀ (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 (<100×10⁹/L)	10%	9%	7%	14%	17%
Heart Transplantation
C₀ (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 (<75×10⁹/L)	5%	5%	6%	8%	9%

Indications

Prophylaxis of kidney and heart transplant rejection 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

Open the list of ICD codes

ICD-10 code	Indication
Z94.0	Presence of transplanted kidney
Z94.1	Presence of transplanted heart
Z94.4	Presence of transplanted liver

ICD-11 code	Indication
QB63.0	Presence of transplanted kidney
QB63.1	Presence of transplanted heart
QB63.3	Presence of transplanted liver

Dosage Regimen

The method of application and dosage regimen for a specific drug depend on its form of release and other factors. The optimal dosage regimen is determined by the doctor. It is necessary to strictly adhere to the compliance of the dosage form of a specific drug with the indications for use and 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.

Take at the same time as cyclosporine in a special dosage form.

Adjustment of the everolimus dosing regimen may be required based on the achieved plasma concentrations, tolerability, individual response to treatment, changes in concomitant drug therapy, and the clinical situation.

Adjustment of the dosing regimen can be carried out at intervals of 4-5 days.

As an antitumor agent, it is used at a dose of 10 mg once daily daily.

Treatment is carried out 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 common – leukopenia; common – 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 common – hypercholesterolemia, hyperlipidemia; common – hypertriglyceridemia.

From the cardiovascular system: common – increased blood pressure, lymphocele, venous thrombosis.

From the respiratory system: common – pneumonia; sometimes – pneumonitis.

From the digestive system: common – abdominal pain, diarrhea, nausea, vomiting; sometimes – hepatitis, liver dysfunction, jaundice, increased ALT, AST, GGT.

From the skin and subcutaneous tissue: common – angioedema, acne, surgical wound complications; sometimes – rash.

From the musculoskeletal system: sometimes – myalgia.

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

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

In controlled clinical studies in which patients were observed for at least one year, the occurrence of lymphoma 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.

It has been shown that Everolimus and/or its metabolites 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.

It is recommended to monitor everolimus concentrations in whole blood 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 the development of 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 influenced 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 the plasma concentrations of drugs eliminated by these enzymes.

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

In a drug interaction study in healthy volunteers who received prior therapy with multiple doses of rifampicin (a CYP3A4 inducer), subsequent administration of a single dose of everolimus resulted in an almost 3-fold increase in the clearance of everolimus 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 antifungal agents: 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 decrease everolimus blood concentrations, including 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 the consumption of these juices should be avoided during the use of everolimus.

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

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.

Medical Disclaimer