Nikolimus (Tablets) Instructions for Use

Marketing Authorization Holder

Pharmasintez-Nord, JSC (Russia)

Manufactured By

Pharmasintez, JSC (Russia)

Or

Pharmasintez-Nord, JSC (Russia)

ATC Code

L01EG02 (Everolimus)

Active Substance

Everolimus (Rec.INN registered by WHO)

Dosage Forms

	Nikolimus	Tablets 2.5 mg: 30 pcs.
		Tablets 5 mg: 30 pcs.
		Tablets 10 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Tablets from white to white with a yellowish tint, round, flat-cylindrical, with a bevel and a score.

Excipients: butylhydroxytoluene – 0.05 mg, hypromellose E15 – 22.5 mg, colloidal silicon dioxide – 2.5 mg, crospovidone – 25 mg, lactose monohydrate – 5 mg, anhydrous lactose – 50 mg, sodium stearyl fumarate – 0.75 mg, microcrystalline cellulose type 112 – 16.7 mg.

10 pcs. – blister packs (3) – cardboard packs.

Tablets from white to white with a yellowish tint, round, flat-cylindrical, with a bevel.

Excipients: butylhydroxytoluene – 0.1 mg, hypromellose E15 – 45 mg, colloidal silicon dioxide – 5 mg, crospovidone – 50 mg, lactose monohydrate – 10 mg, anhydrous lactose – 100 mg, sodium stearyl fumarate – 1.5 mg, microcrystalline cellulose type 112 – 33.4 mg.

10 pcs. – blister packs (3) – cardboard packs.

Tablets from white to white with a yellowish tint, biconvex, capsule-shaped.

Excipients: butylhydroxytoluene – 0.2 mg, hypromellose E15 – 90 mg, colloidal silicon dioxide – 10 mg, crospovidone – 100 mg, lactose monohydrate – 20 mg, anhydrous lactose – 200 mg, sodium stearyl fumarate – 3 mg, microcrystalline cellulose type 112 – 66.8 mg.

10 pcs. – blister packs (3) – cardboard packs.

Clinical-Pharmacological Group

Antitumor drug. Protein kinase inhibitor

Pharmacotherapeutic Group

Antineoplastic agents; protein kinase inhibitors; mTOR kinase (mammalian target of rapamycin) inhibitors

Pharmacological Action

Everolimus is a selective inhibitor of the serine-threonine kinase mTOR (mammalian target of rapamycin), specifically targeting the mTORC1 complex, the signal-transducing mTOR kinase, and the regulatory raptor protein (regulatory associated protein of mTOR). Everolimus exerts its activity through high-affinity interaction with the intracellular receptor protein FKBP12. The FKBP12-Everolimus complex binds to mTORC1, inhibiting its signaling ability. mTOR is a key serine-threonine kinase that plays a central role in regulating cell growth, proliferation, and survival. Regulation of the mTORC1 signaling pathway is a complex process dependent on mitogens, growth factors, energy status, and nutrients.

The mTORC1 complex is a critical regulator of protein synthesis in the distal part of the PI3K/AKT-dependent cascade, the regulation of which is disrupted in most human malignant tumors, as well as in genetic diseases such as tuberous sclerosis (TS).

The signaling function of mTORC1 is realized through modulation of the phosphorylation of distal effectors, among which the translation regulators are best characterized: ribosomal protein S6 kinase (S6K1) and eukaryotic initiation factor 4E-binding protein (4E-BP1). Impaired function of S6K1 and 4E-BP1 due to mTORC1 inhibition disrupts the translation of mRNAs encoding key proteins involved in cell cycle regulation, glycolysis, and cell adaptation to low oxygen levels (hypoxia). This suppresses tumor growth and the expression of hypoxia-inducible factors (e.g., transcription factor HIF-1). The latter leads to reduced expression of factors that enhance angiogenesis in the tumor (e.g., vascular endothelial growth factor, VEGF) in multiple tumors such as renal cell carcinoma and angiomyolipoma. Signaling through mTORC1 is regulated by tumor suppressor genes: tuberous sclerosis genes 1 and 2 (TSC1, TSC2). Absence or inactivation of TSC1 or TSC2 leads to increased levels of RHEB-GTP (Ras homolog enriched in brain guanosine triphosphate-binding protein), which interacts with the mTORC1 complex, causing its activation. Activation of mTORC1 leads to a downstream kinase signaling cascade, including activation of S6K1. The mTORC1 substrate, S6K1, phosphorylates the estrogen receptor, which is responsible for ligand-independent receptor activation.

Everolimus is a potent inhibitor of the growth and proliferation of tumor cells, endothelial cells, fibroblasts, and vascular smooth muscle cells.

Accordingly, due to the central regulatory action of the mTORC1 complex, Everolimus reduces cell proliferation, glycolysis, and angiogenesis in solid tumors in vivo, thus realizing two independent pathways of tumor growth suppression: direct antitumor activity and inhibition of the tumor stromal component.

Activation of the mTOR signaling pathway is a key adaptive mechanism for the development of resistance to endocrine therapy in patients with breast cancer. Various signaling pathways are activated during the development of resistance to endocrine therapy. The main one is the PI3K/AKT/mTOR pathway, which is activated in breast cancer cells resistant to aromatase inhibitors and chronically exposed to estrogen deprivation. Resistance of breast cancer cells to aromatase inhibitors due to AKT activation can be overcome by combination with everolimus. Combination therapy with everolimus and an aromatase inhibitor increases the median progression-free survival by 2.7 times and reduces the probability of disease progression and death by 62%.

In TS, a genetically determined disease, inactivating mutations in the TSC1 or TSC2 genes lead to the formation of hamartomas in various locations.

In patients with subependymal giant cell astrocytomas (SEGA) associated with TS, after 6 months of treatment with everolimus, a statistically significant reduction in tumor volume was observed, with 75% of patients experiencing a tumor volume reduction of at least 30%, and 32% of patients experiencing a reduction of at least 50%. No new lesions, worsening hydrocephalus, signs of increased intracranial pressure, or need for surgical treatment of SEGA occurred. Long-term follow-up of patients with SEGA associated with TS confirmed the sustained efficacy of everolimus.

Pharmacokinetics

After oral administration, C_max is reached within 1-2 hours. C_max changes proportionally to the dose in the dose range from 5 mg to 10 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, binding to plasma proteins is approximately 74%. 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 is mainly found in the systemic circulation.

T_1/2 is about 30 hours. After administration of a single dose of radioactively labeled everolimus to 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.

Indications

Advanced and/or metastatic renal cell carcinoma after failure of antiangiogenic therapy.

Hormone receptor-positive advanced breast cancer in postmenopausal women in combination with an aromatase inhibitor after prior endocrine therapy.

Subependymal giant cell astrocytomas (SEGA) associated with tuberous sclerosis in patients aged 3 years and older when surgical resection of the tumor is not possible.

Renal angiomyolipoma associated with tuberous sclerosis that does not require immediate surgical intervention.

ICD codes

Dosage Regimen

Take orally once daily at approximately the same time each day.

Swallow tablets whole with a glass of water; do not chew or crush.

For advanced renal cell carcinoma and hormone receptor-positive advanced breast cancer in postmenopausal women, the recommended adult dose is 10 mg once daily.

For subependymal giant cell astrocytoma (SEGA) and renal angiomyolipoma associated with tuberous sclerosis, the recommended starting dose for patients aged 3 years and older is 4.5 mg/m² once daily.

Calculate the body surface area (BSA) for pediatric patients and round the dose to the nearest available tablet strength (2.5 mg, 5 mg, or 10 mg).

Adjust the dose to achieve and maintain trough concentration of 5-15 ng/mL for SEGA patients; monitor levels every 3-6 months after stabilization.

For patients with moderate hepatic impairment (Child-Pugh class B), reduce the dose to 5 mg once daily.

For patients with severe hepatic impairment (Child-Pugh class C), reduce the dose to 2.5 mg once daily; if tolerated, consider increasing to 5 mg.

No dose adjustment is required for patients with renal impairment.

Manage adverse reactions with dose reduction or temporary therapy interruption; do not exceed the 10 mg daily dose.

Administer consistently either with food or without food.

Do not administer with grapefruit or grapefruit juice.

Adverse Reactions

Infections and infestations very common – often – pneumonia, urinary tract infections; uncommon – bronchitis, herpes zoster, sepsis, abscess; rare – viral myocarditis; in isolated cases – opportunistic infections (e.g., aspergillosis, candidiasis, viral hepatitis B).

Blood and lymphatic system disorders very common – anemia; common – thrombocytopenia, neutropenia, leukopenia, lymphopenia; uncommon – pancytopenia; rare – true red cell aplasia of the bone marrow.

Immune system disorders uncommon – hypersensitivity reactions.

Metabolism and nutrition disorders very common – decreased appetite, hyperglycemia, hypercholesterolemia; common – hypertriglyceridemia, hypophosphatemia, diabetes mellitus, hyperlipidemia, hypokalemia, dehydration, hypocalcemia.

Psychiatric disorders common – insomnia.

Nervous system disorders very common – taste perception disturbance, headache; uncommon – loss of taste sensitivity.

Eye disorders common – eyelid edema; uncommon – conjunctivitis.

Cardiac disorders common – arterial hypertension, bleeding of various locations, lymphedema; uncommon – chronic heart failure, hot flashes, deep vein thrombosis.

Respiratory, thoracic and mediastinal disorders common – pneumonitis, interstitial lung disease, lung infiltration; rare – alveolar pulmonary hemorrhage, pulmonary toxicity, alveolitis, epistaxis, cough, dyspnea; uncommon – hemoptysis, pulmonary embolism; rare – acute respiratory distress syndrome.

Gastrointestinal disorders very common – stomatitis (including aphthous stomatitis, ulceration of the tongue and oral mucosa, glossitis, glossodynia), diarrhea, nausea; common – vomiting, dry mouth, oral pain, abdominal pain, dyspepsia, dysphagia, weight loss.

Skin and subcutaneous tissue disorders very common – skin rash, pruritus; common – dry skin, nail plate disorders, acneiform rash, erythema, skin desquamation, increased nail brittleness, palmar-plantar erythrodysesthesia syndrome, alopecia; rare – angioedema.

Musculoskeletal and connective tissue disorders common – arthralgia.

Renal and urinary disorders common – proteinuria, renal failure; uncommon – frequent daytime urination, acute renal failure.

Reproductive system and breast disorders common – irregular menstrual cycle; uncommon – amenorrhea.

General disorders and administration site conditions very common – increased fatigue, asthenia, peripheral edema; common – pyrexia, mucosal inflammation; uncommon – non-cardiac chest pain, slow wound healing.

Laboratory data very common – decreased hemoglobin concentration, lymphopenia, leukopenia, thrombocytopenia, neutropenia (or their combination pancytopenia), increased fasting blood glucose, cholesterol, triglycerides, increased AST activity, hypophosphatemia, increased ALT activity, increased creatinine concentration, hypokalemia, decreased albumin concentration.

Contraindications

Hypersensitivity to everolimus, other rapamycin derivatives; children and adolescents under 18 years of age, except for patients under 3 years of age with SEGA; impaired liver function (class A, B, C according to Child-Pugh classification) in patients from 3 to 18 years of age with SEGA; pregnancy, breastfeeding period; simultaneous use of everolimus with potent inhibitors of the CYP3A4 isoenzyme and/or P-glycoprotein; simultaneous use of everolimus with potent inducers of the CYP3A4 isoenzyme and/or inducers of P-glycoprotein.

With caution

When using everolimus simultaneously with moderate CYP3A4 inhibitors or P-glycoprotein inhibitors; in patients over 18 years of age with severe hepatic impairment (class C according to Child-Pugh classification) when the benefit of using this drug outweighs the possible risk; in patients before and after surgical interventions; in patients during or shortly after radiation therapy.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

During therapy with everolimus and for at least 8 weeks after its completion, reliable methods of contraception should be used.

Use in Hepatic Impairment

Not recommended for use in patients under 18 years of age with SEGA and impaired liver function.

In case of impaired liver function, dose adjustment is required.

Use in Renal Impairment

No dose adjustment is required.

Pediatric Use

Treatment of oncological diseases in children and adolescents under 18 years of age is not indicated.

Treatment of children and adolescents under 18 years of age with renal angiomyolipoma associated with TS is not indicated.

Treatment of children under 3 years of age with SEGA with everolimus in tablet form is not indicated; for this category of patients, Everolimus in the form of dispersible tablets should be used.

Not recommended for use in patients under 18 years of age with SEGA and impaired liver function.

Geriatric Use

No dose adjustment is required.

Special Precautions

Treatment should be carried out only under the supervision of a physician experienced in working with antitumor drugs or in the treatment of patients with TS.

Non-infectious pneumonitis is a class-specific side effect of rapamycin derivatives. The diagnosis of non-infectious pneumonitis should be suspected in patients who develop such nonspecific respiratory manifestations as hypoxia, pleural effusion, cough, or dyspnea, and when infectious, tumor, and other causes of such manifestations are excluded by appropriate diagnostic studies. When conducting differential diagnosis of non-infectious pneumonitis, opportunistic infections, such as pneumocystis pneumonia, should be excluded.

The patient should be instructed to report to the attending physician the appearance of any new or worsening of existing respiratory symptoms. In patients who have only radiological signs of non-infectious pneumonitis (in the absence or presence of minimal clinically significant symptoms), it is possible to continue treatment with everolimus without dose adjustment. If the symptoms of pneumonitis are moderate, it is necessary to consider temporarily suspending therapy until the condition improves. Glucocorticoids may be used to relieve symptoms. Everolimus treatment can be resumed at a dose 50% lower than the original dose.

In patients receiving glucocorticoid drugs for the treatment of non-infectious pneumonitis, the possibility of prophylaxis for pneumocystis pneumonia should be considered.

The patient should be informed about the increased risk of infections when using everolimus, to be attentive to the symptoms and signs of infections and to consult a doctor promptly if they appear. In patients with infectious diseases, appropriate treatment should be carried out before using everolimus. If an infectious lesion is confirmed, appropriate therapy should be started immediately and the issue of temporarily suspending or completely discontinuing everolimus therapy should be considered.

In case of invasive systemic fungal infection, everolimus therapy should be discontinued and appropriate antifungal therapy should be administered.

In case of simultaneous treatment with glucocorticoids or other drugs that suppress the immune system, the possibility of prophylaxis for pneumocystis pneumonia should be considered.

In case of stomatitis, the use of local therapy is recommended. The use of agents containing alcohol, hydrogen peroxide, iodine, thyme should be avoided, as they may worsen the condition. Antifungal agents should not be used unless a fungal infection is confirmed.

Renal function should be monitored during everolimus therapy, especially in patients with additional risk factors.

Before starting everolimus treatment and periodically during therapy, renal function should be monitored, including measurement of serum urea concentration, urine protein concentration or serum creatinine concentration, complete blood count should be performed, and everolimus concentration should be determined in patients with SEGA.

Before starting everolimus treatment and periodically during therapy, fasting serum glucose concentration should be monitored. More frequent monitoring is recommended in patients simultaneously receiving other drugs that provoke hyperglycemia. Adequate blood glucose control should be ensured before starting everolimus treatment.

Before starting treatment with everolimus and periodically during therapy, plasma cholesterol and triglyceride concentrations should be monitored. If these indicators deviate from the norm, the use of appropriate therapeutic agents is recommended.

A complete blood count must be performed before starting therapy and periodically throughout the entire course of treatment.

The use of live vaccines and close contact with individuals vaccinated with live vaccines should be avoided. When using everolimus in patients under 18 years of age, all antiviral vaccinations recommended by the local vaccination schedule should be administered.

Severe reactions to radiation therapy (including radiation esophagitis, radiation pneumonitis, and radiation skin injury) have been reported with the use of everolimus during or shortly after radiation therapy. Caution is necessary in this category of patients. Local inflammatory reactions in previously irradiated areas have been reported in patients taking Everolimus after prior radiation therapy.

Effect on the Ability to Drive Vehicles and Operate Machinery

Studies on the effect of everolimus on the ability to drive vehicles and operate machinery have not been conducted. Given the possibility of developing some adverse reactions while taking everolimus (fatigue, dizziness, drowsiness), patients should exercise caution when driving vehicles and engaging in other potentially hazardous activities that require increased concentration.

Drug Interactions

The absorption and subsequent elimination of everolimus can be influenced by drugs that interact with CYP3A4 and/or P-glycoprotein. The concomitant use of everolimus with strong CYP3A4 inhibitors or inducers 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 use 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).

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

In patients receiving concomitant treatment with ACE inhibitors, there may be an increased risk of developing angioedema (e.g., swelling of the airways or tongue with/without impaired respiratory function).

Grapefruit and grapefruit juice affect the activity of CYP isoenzymes and P-glycoprotein, so consumption of these juices should be avoided while taking 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.