Everolimus-teva

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT EVEROLIMUS-TEVA

Composition:

Active substance: everolimus;

1 tablet contains 2.5 mg or 5 mg or 10 mg of everolimus;

Excipients: butylhydroxytoluene (E 321), hypromellose (type 2910, 3 mPa·s), lactose monohydrate (450 M), anhydrous lactose, crospovidone (type A), magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

2.5 mg tablets: white, elongated, flat tablets with beveled edges, marked with "EV" on one side and "2.5" on the other. Size approximately 10 × 4 mm;

5 mg tablets: white, elongated, flat tablets with beveled edges, marked with "EV" on one side and "5" on the other. Size approximately 12 × 5 mm;

10 mg tablets: white, elongated, flat tablets with beveled edges, marked with "EV" on one side and "10" on the other. Size approximately 15 × 6 mm.

Pharmacotherapeutic group. Antineoplastic and immunomodulating agents. Antineoplastic agents. Protein kinase inhibitors. Mammalian target of rapamycin (mTOR) kinase inhibitors. Everolimus. ATC code L01E G02.

Pharmacological Properties

Pharmacodynamics

Everolimus is a selective inhibitor of mTOR (mammalian target of rapamycin). mTOR is a key serine-threonine kinase that is activated in a number of human cancers. Everolimus binds to the intracellular protein FKBP-12, forming a complex that inhibits the activity of the mTOR complex-1 (mTORC1). Inhibition of the mTORC1 signaling pathway disrupts protein translation and synthesis by reducing the activity of ribosomal protein S6 kinase (S6K1) and the eukaryotic elongation factor 4E-binding protein (4EBP-1), thereby regulating proteins involved in the cell cycle, angiogenesis, and glycolysis. S6K1 is believed to phosphorylate domain 1 of the estrogen receptor activation function, which mediates ligand-independent receptor activation. Everolimus reduces levels of vascular endothelial growth factor (VEGF), which promotes tumor angiogenesis. Everolimus is a potent inhibitor of tumor cell growth and proliferation, as well as of endothelial cells, fibroblasts, and vascular smooth muscle cells; it reduces glycolysis in solid tumors both in vitro and in vivo.

Pharmacokinetics

Absorption. In patients with advanced solid tumors, maximum everolimus concentration (C_max) is reached at a median time of 1 hour following daily administration of 5 mg or 10 mg everolimus under fasting conditions or with a low-fat meal. C_max values are dose-proportional within the dose range of 5 mg to 10 mg. Everolimus is a substrate and moderate inhibitor of P-glycoprotein (P-gp).

Effect of Food. In healthy volunteers, a high-fat meal reduced the area under the plasma concentration-time curve (AUC) of 10 mg everolimus by 22% and C_max by 54%. A low-fat meal reduced AUC by 32% and C_max by 42%. However, food did not affect AUC during the post-absorption phase.

Distribution. The blood-to-plasma ratio of everolimus, concentration-dependent within the range of 5 to 5000 ng/mL, is 17–73%. In cancer patients receiving 10 mg daily, approximately 20% of total everolimus concentration in whole blood is present in plasma. Plasma protein binding is approximately 74% in both healthy volunteers and patients with moderate hepatic impairment. In patients with advanced solid tumors, the mean steady-state volume of distribution (V_d) was 191 L for the apparent central compartment and 517 L for the apparent peripheral compartment.

Biotransformation. Everolimus is a substrate of CYP3A4 and P-gp. Following oral administration, everolimus is the predominant circulating component in human blood. Six major metabolites of everolimus have been identified in human blood, including three monohydroxylated metabolites, two hydroxylated ring-opened products, and a phosphatidylcholine conjugate of everolimus. These metabolites have also been detected in animals in toxicity studies. The activity of these metabolites is approximately 100-fold lower than that of everolimus. Therefore, everolimus is primarily responsible for the overall pharmacological activity.

Elimination. The mean oral clearance (CL/F) of everolimus after a daily dose of 10 mg in patients with advanced solid tumors was 24.5 L/h. The mean elimination half-life of everolimus was approximately 30 hours.

Specific elimination studies have not been conducted in cancer patients, but data from studies in transplant patients are available. After a single oral dose of radiolabeled everolimus co-administered with cyclosporine, 80% of radioactivity was recovered in feces and 5% in urine. The unchanged parent compound was not detected in urine or feces.

Steady-state Pharmacokinetics. Following administration of everolimus to patients with advanced solid tumors, steady-state AUC_0–τ was dose-proportional over the range of 5 to 10 mg daily. Steady state was achieved within 2 weeks. C_max was dose-proportional in the dose range of 5–10 mg. Time to maximum concentration (T_max) occurred 1–2 hours after dosing. A significant correlation was observed between AUC_0–τ and the trough concentration at steady state.

Special Patient Populations

Hepatic Impairment. The safety, tolerability, and pharmacokinetics of everolimus were evaluated in two studies of single oral doses of everolimus tablets involving 8 and 34 patients with hepatic impairment compared to individuals with normal liver function. In the first study, mean AUC of everolimus in 8 patients with moderate hepatic impairment (Child-Pugh class B) was twice that in 8 individuals with normal liver function. In the second study involving 34 individuals with varying degrees of hepatic impairment, exposure (i.e., AUC_0–inf) was increased by 1.6-, 3.3-, and 3.6-fold, respectively, in patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment compared to healthy volunteers. Pharmacokinetic modeling of multiple-dose administration supports dose recommendations for patients with hepatic dysfunction based on their Child-Pugh classification. Based on the results of these two studies, dose adjustment is recommended for patients with hepatic impairment.

Renal Impairment. In a population pharmacokinetic analysis of 170 patients with advanced solid tumors, no significant effect of creatinine clearance (25–178 mL/min) on CL/F of everolimus was observed. Renal impairment following transplantation (creatinine clearance range 11–107 mL/min) did not affect the pharmacokinetics of everolimus in transplant patients.

Elderly Patients. In population pharmacokinetic assessment of oncology patients, no significant effect of age (27–85 years) on oral clearance of everolimus was observed.

Ethnicity. Oral clearance (CL/F) is similar in Japanese and Caucasian patients with comparable liver function. Population pharmacokinetic analysis has shown that oral clearance (CL/F) in post-transplant patients of Black race is on average 20% higher than in other racial groups.

Clinical characteristics.

Indications.

Hormone receptor-positive advanced breast cancer

The medicinal product Everolimus-Teva is indicated for the treatment in combination with exemestane of hormone receptor-positive, HER2/neu-negative advanced breast cancer in postmenopausal women without symptomatic visceral disease in cases of recurrence or progression following therapy with nonsteroidal aromatase inhibitors.

Pancreatic neuroendocrine tumors

The medicinal product Everolimus-Teva is indicated for the treatment of unresectable or metastatic, well-differentiated or moderately differentiated neuroendocrine tumors of pancreatic origin in adults with progressive disease.

Gastrointestinal or lung neuroendocrine tumors

The medicinal product Everolimus-Teva is indicated for the treatment of unresectable or metastatic, well-differentiated (Grade 1 or Grade 2) non-functional neuroendocrine tumors of gastrointestinal or lung origin in adults with progressive disease.

Renal cell carcinoma

The medicinal product Everolimus-Teva is indicated for the treatment of patients with progressive renal cell carcinoma whose disease has progressed on or after VEGF-targeted therapy.

Contraindications.

Hypersensitivity to the active substance, other derivatives of sirolimus, or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Everolimus is a substrate of CYP3A4 and also a substrate and moderate inhibitor of PgP. Therefore, substances affecting CYP3A4 and/or PgP may influence the absorption and subsequent elimination of everolimus. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6. Known and theoretical interactions with specific inhibitors and inducers of CYP3A4 and PgP are presented in Table 1.

Inhibitors of CYP3A4 and PgP that increase everolimus concentration. Substances that are inhibitors of CYP3A4 or PgP may increase everolimus blood concentrations by reducing its metabolism or efflux from intestinal cells.

Inducers of CYP3A4 and PgP that decrease everolimus concentration. Substances that are inducers of CYP3A4 or PgP may reduce everolimus blood concentrations by increasing its metabolism or efflux from intestinal cells.

Table 1

Effect of other active substances on everolimus

Drugs whose plasma concentrations may be altered by everolimus. Based on in vitro data, it is unlikely that systemic concentrations achieved after oral daily doses of 10 mg will lead to inhibition of PgP, CYP3A4, and CYP2D6. However, inhibition of intestinal CYP3A4 and PgP cannot be excluded. A drug interaction study in healthy volunteers showed that concomitant administration of oral midazolam, a sensitive CYP3A substrate probe, with everolimus increased midazolam Cmax by 25% and AUC(0-inf) by 30%. This effect is likely due to inhibition of intestinal CYP3A4 by everolimus. Therefore, when administered concomitantly, everolimus may affect the bioavailability of oral CYP3A4 substrates. However, clinically relevant effects on systemic exposure to CYP3A4 substrates are not expected. Concomitant administration of everolimus and depot octreotide increased the minimum concentration (Cmin) of octreotide, with a geometric mean ratio (everolimus/placebo) of 1.47. A clinically significant impact on the efficacy response to everolimus in patients with progressive neuroendocrine tumors could not be established. Concomitant administration of everolimus with exemestane increased Cmin and C2h of exemestane by 45% and 64%, respectively. However, corresponding estradiol levels at steady state (4 weeks) did not differ between the two treatment groups. In patients with hormone receptor-positive, progressive breast cancer receiving this combination, no increase in the frequency of adverse reactions associated with exemestane was observed. It is unlikely that increased exemestane levels will affect efficacy or safety.

Concomitant use of angiotensin-converting enzyme (ACE) inhibitors. Patients receiving an ACE inhibitor (e.g., ramipril) concomitantly have an increased risk of angioedema (see section "Special precautions").

Vaccination. Immune response to vaccines may be altered; therefore, vaccination may be less effective during treatment with everolimus. Live vaccines should be avoided during treatment with Everolimus-Teva. Examples of live vaccines include intranasal influenza vaccine, measles-mumps-rubella vaccine, oral poliovirus vaccine, BCG (Bacillus Calmette-Guérin) vaccine, yellow fever vaccine, varicella vaccine, and typhoid vaccine TY21a.

Radiation therapy. Enhanced toxicity of radiation therapy has been observed in patients receiving everolimus.

Special precautions for use.

Non-infectious pneumonitis. Non-infectious pneumonitis is a class-effect of rapamycin derivatives, including everolimus. Non-infectious pneumonitis (including interstitial lung disease) has been frequently observed in patients receiving everolimus. Some cases were severe and rarely fatal. The diagnosis of non-infectious pneumonitis should be considered in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, after appropriate investigations have excluded infections, neoplasms, or other non-drug-related causes. In differential diagnosis of non-infectious pneumonitis, opportunistic infections such as Pneumocystis jirovecii (carinii) pneumonia (PJP, PCP) must be ruled out. Patients should be advised to promptly report any new respiratory symptoms or worsening of existing ones. Patients with radiological findings suggestive of non-infectious pneumonitis but with minimal or no symptoms may continue treatment with Everolimus-Teva without dose adjustment. If symptoms are moderate (Grade 2) or severe (Grade 3), corticosteroid therapy may be indicated until clinical symptoms resolve. For patients requiring corticosteroids to treat non-infectious pneumonitis, prophylaxis against Pneumocystis jirovecii (carinii) pneumonia (PJP, PCP) should be considered.

Infections. Everolimus has immunosuppressive properties and may predispose to bacterial, fungal, viral, or protozoal infections, including opportunistic pathogens. Local and systemic infections, including pneumonia, other bacterial infections, invasive fungal infections (such as aspergillosis, candidiasis, or Pneumocystis jirovecii (carinii) pneumonia (PJP, PCP)), and viral infections (including reactivation of hepatitis B virus), have been observed in patients receiving everolimus. Some of these infections were severe (leading to sepsis, respiratory or hepatic failure) and occasionally fatal. Physicians and patients should remain aware of the increased risk of infections during everolimus therapy. Pre-existing infections should be adequately treated and fully resolved prior to initiating everolimus. Close monitoring for signs and symptoms of infection is required during treatment with Everolimus-Teva. If an infection is diagnosed, appropriate therapy should be initiated promptly, and temporary or permanent discontinuation of everolimus should be considered. In case of invasive systemic fungal infection, everolimus treatment should be immediately and permanently discontinued, and appropriate antifungal therapy initiated. Cases of Pneumocystis jirovecii (carinii) pneumonia (PJP, PCP), sometimes fatal, have been reported with everolimus use. The development of PJP/PCP may be associated with concomitant use of corticosteroids or other immunosuppressive agents. Prophylaxis against PJP/PCP should be considered if concomitant use of corticosteroids or other immunosuppressants is required.

Hypersensitivity reactions. Hypersensitivity reactions have been observed with everolimus, manifesting as symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, chest pain, and angioedema (e.g., airway or tongue swelling, with or without respiratory distress).

Concomitant use of angiotensin-converting enzyme inhibitors (ACE inhibitors). Patients receiving concomitant ACE inhibitors (e.g., ramipril) may have an increased risk of angioedema (i.e., swelling of the airways or tongue, with or without respiratory distress).

Stomatitis. Stomatitis, including oral ulcers and oral mucositis, is the most common adverse reaction in patients treated with everolimus. Stomatitis predominantly occurs during the first 8 weeks of treatment. A study in a cohort of postmenopausal women with breast cancer receiving everolimus and exemestane showed that a non-alcoholic corticosteroid oral solution used as a mouthwash during the first 8 weeks of treatment may reduce the frequency and severity of stomatitis. Therefore, stomatitis management may include prophylactic and/or therapeutic use of a non-alcoholic corticosteroid oral rinse. However, alcohol-containing solutions, hydrogen peroxide, iodine, and thyme derivatives should be avoided, as they may exacerbate the condition. Monitoring and treatment of fungal infections are recommended, particularly in patients receiving corticosteroid medications. Antifungal agents should not be used prior to diagnosis of a fungal infection.

Renal impairment. Cases of renal failure (including acute renal failure), some fatal, have been reported in patients receiving everolimus. Renal function should be monitored, especially in patients with additional risk factors that may further impair kidney function.

Laboratory tests and monitoring.

Renal function. Increases in serum creatinine, usually mild, and proteinuria have been reported. Renal function, including blood urea nitrogen (BUN), urinary protein, or serum creatinine, should be monitored before starting everolimus treatment and periodically thereafter.

Blood glucose. Hyperglycemia has been reported. Fasting serum glucose should be monitored before starting Everolimus-Teva and periodically thereafter. More frequent monitoring is recommended when Everolimus-Teva is used concomitantly with other medications that may cause hyperglycemia. Optimal glycemic control should be achieved, if possible, before initiating treatment with Everolimus-Teva.

Blood lipids. Dyslipidemia (including hypercholesterolemia and hypertriglyceridemia) has been reported. Cholesterol and triglyceride levels should be monitored before starting Everolimus-Teva and periodically thereafter, with appropriate pharmacological therapy initiated as needed.

Hematological parameters. Decreases in hemoglobin, lymphocytes, neutrophils, and platelets have been reported. Complete blood count should be monitored before starting everolimus treatment and periodically thereafter.

Functional carcinoid tumors. In a randomized, double-blind, multicenter study of patients with functional carcinoid tumors, everolimus plus octreotide depot was compared with placebo plus octreotide depot. This study did not meet its primary efficacy endpoint (interim analysis of progression-free survival [PFS] and overall survival [OS] numerically favored the placebo plus octreotide depot group). Therefore, the safety and efficacy of everolimus in patients with functional carcinoid tumors have not been established.

Prognostic factors for gastroenteropancreatic or pulmonary neuroendocrine tumors. In patients with non-functional gastroenteropancreatic or pulmonary neuroendocrine tumors and favorable baseline prognostic factors—i.e., primary tumor originating in the ileum and normal chromogranin A levels or absence of bone involvement—an individual benefit-risk assessment should be performed before initiating therapy with Everolimus-Teva. Limited data on progression-free survival benefit were observed in the subgroup of patients with ileal primary tumors.

Interactions. Concomitant use with CYP3A4 inhibitors and inducers and/or P-glycoprotein (PgP) efflux pump substrates should be avoided. If concomitant use with moderate CYP3A4 and/or PgP inhibitors or inducers cannot be avoided, patients should be closely monitored clinically. Dose adjustment of Everolimus-Teva may be considered based on predicted AUC. Concomitant use with strong CYP3A4/PgP inhibitors significantly increases everolimus plasma concentrations. Currently, there are insufficient data to provide dosing recommendations in such cases; therefore, concomitant use of Everolimus-Teva with strong CYP3A4/PgP inhibitors is not recommended.

Everolimus-Teva should be used with caution in combination with oral CYP3A4 substrates with a narrow therapeutic index due to the potential for drug interactions. If Everolimus-Teva is administered concomitantly with oral CYP3A4 substrates with a narrow therapeutic index (e.g., pimozide, terfenadine, astemizole, cisapride, quinidine, or ergot alkaloid derivatives), patients should be monitored for adverse reactions described in the prescribing information for these CYP3A4 substrate drugs.

Hepatic impairment. Everolimus exposure increases in patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment. Everolimus-Teva is recommended for use in patients with severe hepatic impairment (Child-Pugh class C) only when the anticipated benefit outweighs the potential risk. Currently, there are no available data on safety and efficacy to support dosing recommendations for managing severe adverse reactions in patients with hepatic impairment.

Vaccination. Live vaccines should be avoided during treatment with everolimus.

Impaired wound healing. Impaired wound healing is a class-effect of rapamycin derivatives, including everolimus. Therefore, caution should be exercised when administering everolimus in the perioperative period.

Complications of radiation therapy. Serious and severe radiation reactions (such as radiation esophagitis, radiation pneumonitis, and radiation dermatitis), including fatal cases, have been reported when everolimus was administered during or shortly after radiotherapy. Therefore, caution should be exercised regarding potential enhancement of radiation toxicity in patients receiving everolimus close in time to radiation therapy.

Additionally, radiation recall syndrome (RRS) has been reported in patients receiving everolimus who had prior radiation therapy. If RRS develops, temporary interruption or discontinuation of everolimus therapy should be considered.

Lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Use during pregnancy or breastfeeding.

Women of reproductive potential/contraception in men and women. Women of reproductive potential should use a highly effective method of contraception (e.g., oral, injectable, or implantable non-estrogen hormonal contraception, progestin-based contraceptives, hysterectomy, tubal ligation, complete abstinence from sexual intercourse, barrier methods, intrauterine device, and/or female/male sterilization) during treatment with everolimus and for 8 weeks after discontinuation of therapy. There are no restrictions for male patients regarding family planning.

Pregnancy. Adequate data on the use of everolimus in pregnant women are lacking. Animal studies have demonstrated reproductive toxicity, including embryotoxicity and fetotoxicity. The potential risk to humans is unknown.

Everolimus is not recommended during pregnancy and in women of childbearing potential who are not using contraception.

Breastfeeding. It is unknown whether everolimus is excreted in human breast milk. However, everolimus and/or its metabolites readily pass into rat milk. Therefore, women taking everolimus should not breastfeed during treatment and for 2 weeks after the last dose.

Fertility. The potential of everolimus to cause infertility in male and female patients is unknown. However, amenorrhea (secondary amenorrhea and other menstrual disorders) and associated luteinizing hormone (LH)/follicle-stimulating hormone (FSH) imbalance have been observed in female patients. Preclinical data suggest that everolimus may impair male and female fertility.

Ability to drive and use machines.

Everolimus may have a minor or moderate influence on the ability to drive or operate machinery. If patients experience increased fatigue during treatment with everolimus, they should be advised to exercise caution when driving or operating machinery.

Dosage and administration.

Treatment with Everolimus-Teva should be initiated and supervised by a physician experienced in the use of anticancer therapies.

Dosage. Everolimus-Teva is available in tablet form in strengths of 2.5 mg, 5 mg, and 10 mg. The recommended dose of everolimus is 10 mg once daily. Treatment should be continued as long as clinical benefit is observed or until unacceptable toxicity occurs.

If a dose is missed, the patient should not take a supplementary dose, but instead take the next scheduled dose at the usual time.

Dose adjustments due to adverse reactions. Management of severe and/or intolerable suspected adverse reactions may require dose reduction and/or temporary interruption of everolimus therapy. Dose adjustment is generally not required for grade 1 adverse reactions. If dose adjustment is necessary, the recommended dose is 5 mg daily, but not less. Table 2 provides dose adjustment recommendations for specific adverse reactions (see section "Special precautions"). General recommendations for patient management are also provided. The physician's clinical judgment determines the management plan for each patient based on an individual assessment of benefit-risk balance.

Table 2

Dose adjustment recommendations for Everolimus-Teva

Elderly patients (≥65 years of age). Dose adjustment is not required.

Renal impairment. Dose adjustment is not required.

Hepatic impairment.

• Mild hepatic impairment (Child-Pugh class A): recommended dose is 7.5 mg once daily.
• Moderate hepatic impairment (Child-Pugh class B): recommended dose is 5 mg once daily.
• Severe hepatic impairment (Child-Pugh class C): everolimus should only be used if the anticipated benefit outweighs the potential risk. In this case, the daily dose should not exceed 2.5 mg.

The dose should be adjusted if the patient's hepatic function status (according to the Child-Pugh scale) changes during treatment.

Method of administration. Everolimus-Teva should be taken orally at the same time each day, consistently with or without food. Everolimus-Teva tablets should be swallowed whole with a glass of water. Tablets must not be chewed or crushed.

Children.

The safety and efficacy of everolimus in children (aged 0 to 18 years) have not been established. Appropriate data are lacking.

Overdose.

Human experience with overdose is very limited. Single doses up to 70 mg have been administered with acceptable acute tolerability. In cases of overdose, general supportive measures should be undertaken.

Adverse reactions.

Summary of safety profile. The safety profile is based on pooled safety data from 2879 patients who received everolimus for approved indications across eleven clinical trials, including five randomized, double-blind, placebo-controlled Phase III trials and six open-label Phase I and Phase II trials.

The most common adverse reactions (frequency ≥ 1/10), based on pooled safety data (in order of decreasing frequency): stomatitis, rash, fatigue, diarrhea, infections, nausea, decreased appetite, anemia, dysgeusia, pneumonitis, peripheral edema, hyperglycemia, asthenia, pruritus, weight loss, hypercholesterolemia, epistaxis, cough, and headache.

The most common adverse reactions of Grade 3–4 (frequency from ≥ 1/100 to < 1/10): stomatitis, anemia, hyperglycemia, infections, fatigue, diarrhea, pneumonitis, asthenia, thrombocytopenia, neutropenia, dyspnea, proteinuria, lymphopenia, hemorrhage, hypophosphatemia, rash, hypertension, pneumonia, increased alanine aminotransferase (ALT), aspartate aminotransferase (AST), and diabetes mellitus. Severity grading corresponds to CTCAE versions 3.0 and 4.03.

The adverse reactions listed below are categorized by frequency and are derived from the pooled safety analysis. Adverse reactions are presented by MedDRA system organ class and frequency categories.

Frequency categories are defined as follows: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data). Within each frequency group, adverse reactions are listed in order of decreasing severity.

Infections and infestations. Very common: infectionsa,*.

Blood and lymphatic system disorders. Very common: anemia. Common: thrombocytopenia, neutropenia, leukopenia, lymphopenia. Uncommon: pancytopenia. Rare: pure red cell aplasia.

Immune system disorders. Uncommon: hypersensitivity.

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: dysgeusia, headache. Uncommon: ageusia.

Eye disorders. Common: eyelid edema. Uncommon: conjunctivitis.

Cardiac disorders. Uncommon: congestive heart failure.

Vascular disorders. Common: hemorrhageb, hypertension, lymphedemag. Uncommon: hot flushes, deep vein thrombosis.

Respiratory, thoracic and mediastinal disorders. Very common: pneumonitisc, epistaxis, cough. Common: dyspnea. Uncommon: hemoptysis, pulmonary embolism. Rare: acute respiratory distress syndrome.

Gastrointestinal disorders. Very common: stomatitisd, diarrhea, nausea. Common: vomiting, dry mouth, abdominal pain, mucosal inflammation, oral pain, dyspepsia, dysphagia.

Hepatobiliary disorders. Common: increased levels of aspartate aminotransferase and alanine aminotransferase.

Skin and subcutaneous tissue disorders. Very common: rash, pruritus. Common: dry skin, nail disorders, moderate alopecia, acne, erythema, onycholysis, hand-foot syndrome, skin desquamation, skin disorders. Rare: angioedema*.

Musculoskeletal and connective tissue disorders. Common: arthralgia.

Renal and urinary disorders. Common: proteinuria*, increased blood creatinine, renal failure*. Uncommon: polyuria, acute renal failure*.

Reproductive system and breast disorders. Common: menstrual irregularitiese. Uncommon: amenorrheae,*.

General disorders and administration site conditions. Very common: fatigue, asthenia, peripheral edema. Common: pyrexia. Uncommon: non-cardiac chest pain, impaired wound healing.

Investigations. Very common: weight decreased.

Injury, poisoning and procedural complications. Frequency not known: radiation recall syndrome (RRS), potentiation of radiation reactionf.

* See also section "Description of selected adverse reactions".

a Includes all events within the system organ class "Infections and infestations", including (common) pneumonia, urinary tract infections; (uncommon) bronchitis, herpes zoster, sepsis, abscess, and individual cases of opportunistic infections [e.g., aspergillosis, candidiasis, Pneumocystis jirovecii (carinii) pneumonia (PJP, PCP), and hepatitis B (see also section "Special warnings and precautions for use")]; and (rare) viral myocarditis.

b Includes various hemorrhage events at different sites not listed separately.

c Includes (very common) pneumonitis, (common) interstitial lung disease, lung infiltration, and (rare) pulmonary alveolar hemorrhage, pulmonary toxicity, and alveolitis.

d Includes (very common) stomatitis, (common) aphthous stomatitis, oral and tongue ulceration, and (uncommon) gingival pain, glossodynia, glossitis.

e Frequency based on number of women aged 10–55 years in pooled data.

f Adverse reactions identified during the post-marketing period.

g Adverse reactions identified based on post-marketing reports. Frequency determined from pooled safety data in oncology trials.

Description of selected adverse reactions. Based on clinical trials and spontaneous reports in the post-marketing period, everolimus has caused severe cases of hepatitis B reactivation, including fatal outcomes. Reactivation of infection is an expected adverse reaction during immunosuppressive periods. Based on clinical trials and spontaneous post-marketing reports, everolimus use has been associated with cases of renal failure (including fatal outcomes), proteinuria, and increased serum creatinine concentration. Monitoring of renal function is recommended. Based on clinical trials and spontaneous post-marketing reports, everolimus use has been associated with cases of amenorrhea (secondary amenorrhea and other menstrual disorders). Based on clinical trials and spontaneous post-marketing reports, everolimus use has been linked to cases of Pneumocystis jirovecii (carinii) pneumonia (PJP, PCP), some with fatal outcomes. Based on clinical trials and spontaneous post-marketing reports, cases of angioedema have occurred during concomitant use of ACE inhibitors as well as in their absence.

Elderly patients. In the pooled safety data, 37% of patients receiving everolimus were aged ≥ 65 years. The proportion of patients with adverse reactions leading to drug discontinuation was higher among patients aged ≥ 65 years (20% vs. 13%). The most common adverse events leading to discontinuation were pneumonitis (including interstitial lung disease), stomatitis, fatigue, and dyspnea.

Reporting of adverse reactions. Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals, pharmacists, patients, or their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy to the State Expert Center of the Ministry of Health of Ukraine via the following link: https://aisf.dec.gov.ua/

Shelf life. 2.5 years.

Storage conditions. Store at temperatures not exceeding 25 °C in the original packaging to protect from light. Keep out of reach of children.

Packaging. Tablets 2.5 or 5 mg: 10 tablets in a blister; 3 blisters in a cardboard box. Tablets 10 mg: 5 tablets in a blister; 6 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. PLIVA Hrvatska d.o.o.

Manufacturer's address and location of business activity. Baron Filipovića 25, 10000 Zagreb, Croatia.