Everonat

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT EVERONAT

Composition:

Active substance: everolimus;

1 tablet contains 5 mg or 10 mg of everolimus;

Excipients: butylhydroxytoluene (E 321); hypromellose; lactose, anhydrous; acetone; crospovidone; magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

5 mg: tablets from white to almost white, oval, flat-shaped, with engraving «EVR» on one side and «5» on the other;

10 mg: tablets from white to almost white, oval, flat-shaped, with engraving «EVR» on one side and «NAT» on the other.

Pharmacotherapeutic group. Antineoplastic agents. Other antineoplastic agents. Protein kinase inhibitors. ATC code L01X E10.

Pharmacological properties.

Pharmacodynamics.

Everolimus is a selective inhibitor of mTOR (mammalian target of rapamycin). mTOR is a key serine-threonine kinase whose activity is increased in the development of many types of human cancers.

Everolimus binds to the intracellular protein FKBP-12, forming a complex that inhibits the mTOR complex-1 (mTORC1). Inhibition of the mTORC1 signaling pathway interferes with translation and protein synthesis by reducing the activity of ribosomal protein kinase S6 (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's activation function, which is responsible for ligand-independent receptor activation. Everolimus reduces levels of vascular endothelial growth factor (VEGF), which promotes tumor angiogenesis. In patients with TSC, everolimus treatment leads to increased VEGF-A concentrations and decreased VEGF-D.

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 concentrations of everolimus (Cmax) are reached at a median time of 1 hour after daily administration of 5 or 10 mg everolimus on an empty stomach or with a light, low-fat meal. Cmax values are dose-proportional in the range of 5 to 10 mg. Everolimus is a substrate and moderate inhibitor of P-glycoprotein (PgP).

Effect of food.

In healthy volunteers, a high-fat meal reduced systemic exposure to 10 mg everolimus (measured by AUC) by 22% and Cmax by 54%. A low-fat meal reduced AUC by 32% and Cmax by 42%.

However, food had no apparent effect on the concentration-time profile during the post-absorption phase.

Distribution.

The blood-to-plasma ratio of everolimus, concentration-dependent in the range of 5 to 5000 ng/mL, ranges from 17 to 73%. The amount of everolimus present in plasma is approximately 20% of the total blood concentration observed in cancer patients receiving 10 mg/day of everolimus. Plasma protein binding is approximately 74% in both healthy volunteers and patients with moderate hepatic impairment.

In patients with advanced solid tumors, the volume of distribution (Vd) was 191 L for the apparent central compartment and 517 L for the apparent peripheral compartment.

Metabolism.

Everolimus is a substrate of CYP3A4 and PgP. After oral administration, everolimus is the main 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 were also detected in animals used in toxicity studies. The activity of these metabolites was approximately 100 times lower than that of everolimus. Therefore, everolimus is primarily responsible for the overall pharmacological activity.

Elimination.

The mean value of CL/F for everolimus after a daily 10 mg dose in patients with advanced solid tumors was 24.5 L/hour. The mean elimination half-life of everolimus is approximately 30 hours.

Specific elimination studies involving oncology patients have not been conducted; however, data from studies in transplant patients are available. After administration of a single radiolabeled dose of everolimus together with cyclosporine, 80% of radioactivity was excreted in feces and 5% in urine. The parent compound was not detected in feces or urine.

Steady-state pharmacokinetics.

After administration of everolimus in patients with advanced solid tumors, steady-state AUC0-τ was dose-proportional over daily doses ranging from 5 to 10 mg. Steady state was achieved within 2 weeks. Cmax values were dose-proportional in the 5 to 10 mg range. tmax occurred at 1–2 hours after dosing. AUC0-τ and pre-dose minimum concentration values showed significant correlation.

Special patient groups.

Hepatic impairment.

The safety, tolerability, and pharmacokinetics of everolimus were evaluated in two studies of single oral doses of everolimus involving 8 and 34 adult patients with hepatic impairment compared to individuals with normal liver function.

In the first study, the mean AUC of everolimus in 8 patients with moderate hepatic impairment (Child–Pugh class B) was twice that observed in 8 patients with normal liver function.

In the second study involving 34 patients with varying degrees of hepatic impairment, drug exposure (i.e., AUC0–inf) in patients with mild (Child–Pugh class A), moderate (Child–Pugh class B), and severe (Child–Pugh class C) hepatic impairment was 1.6, 3.3, and 3.6 times higher, respectively, than in healthy volunteers.

Modeling results of multiple-dose pharmacokinetics support dose adjustment of everolimus in patients with hepatic impairment 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 patients with advanced solid tumors, no significant effect of creatinine clearance (25–178 mL/min) on CL/F of everolimus was observed. Renal impairment after transplantation (creatinine clearance range 11–107 mL/min) did not affect the pharmacokinetics of everolimus in transplant patients.

Elderly patients.

In pharmacokinetic assessments of oncology patients, age (27–85 years) had no significant effect on oral clearance of everolimus.

Ethnicity.

Oral clearance of everolimus (CL/F) is similar in Mongoloid and Caucasian patients with comparable liver function. According to population pharmacokinetic analysis, oral clearance (CL/F) in post-transplant patients of Negroid ethnicity is on average 20% higher.

Clinical characteristics.

Indications.

• Treatment in combination with exemestane of advanced hormone receptor-positive, HER2-negative breast cancer in postmenopausal women without rapidly progressing visceral disease, in whom prior therapy with non-steroidal aromatase inhibitors resulted in recurrence or disease progression.
• Treatment of unresectable or metastatic, well or moderately differentiated pancreatic neuroendocrine tumors in adult patients with progressing disease.
• Treatment of patients with gastrointestinal or lung neuroendocrine tumors. Everonat is indicated for the treatment of unresectable or metastatic, well-differentiated (grade 1 or grade 2), non-functioning gastrointestinal or lung neuroendocrine tumors in adults with progressive disease.
• Treatment of patients with advanced renal cell carcinoma whose disease has progressed on or after VEGF-targeted therapy (vascular endothelial growth factor therapy).

Contraindications.

Hypersensitivity to the active substance, other derivatives of rapamycin, or to any excipient of the medicinal product.

Interaction with other medicinal products and other types of interactions.

Everolimus is a substrate of CYP3A4 and also a substrate and moderate inhibitor of P-glycoprotein (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 potential interactions with certain inhibitors and inducers of CYP3A4 and PgP are listed in Table 1.

Inhibitors of CYP3A4 and PgP that increase everolimus concentration.

Substances that inhibit CYP3A4 or PgP may increase blood concentrations of everolimus by slowing metabolism or efflux of everolimus from intestinal cells.

Inducers of CYP3A4 and PgP that decrease everolimus concentration.

Substances that induce CYP3A4 or PgP may reduce blood concentrations of everolimus by accelerating metabolism or efflux of everolimus from intestinal cells.

Effect of other active substances on everolimus.

Table 1

Active substance by type of interaction		Interaction – change in AUC/Cmax of everolimus Geometric mean ratio (observed range)	Recommendations for concomitant use
Potent inhibitors of CYP3A4/PgP
Ketoconazole		AUC increased by 15.3-fold (range 11.2–22.5). Cmax increased by 4.1-fold (range 2.6–7).	Concomitant use of Everonat and potent inhibitors is not recommended.
Itraconazole, posaconazole, voriconazole		Not studied. A significant increase in everolimus concentration is possible.
Telithromycin, clarithromycin
Nefazodone
Ritonavir, atazanavir, saxquinavir, darunavir, indinavir, nelfinavir
Moderate inhibitors of CYP3A4/PgP
Erythromycin	AUC increased by 4.4-fold (range 2–12.6). Cmax increased by 2-fold (range 0.9–3.5).		If concomitant use of moderate CYP3A4 or PgP inhibitors cannot be avoided, caution should be exercised. If a patient requires concomitant use of a moderate CYP3A4 or PgP inhibitor, dose reduction to 5 mg or 2.5 mg daily may be considered. However, clinical data on such dose adjustment are lacking. Due to inter-individual variability, the recommended dose adjustment may not be optimal for all patients; therefore, careful monitoring for adverse effects is recommended (see sections “Dosage and administration” and “Special precautions”). If concomitant use of a moderate inhibitor is discontinued, the elimination period of the drug should be considered to be at least 2–3 days (the average elimination time for most commonly used moderate inhibitors), and only after this period should Everonat be resumed at the dose previously used before starting the concomitant therapy.
Imatinib	AUC increased by 3.7-fold. Cmax increased by 2.2-fold.
Verapamil	AUC increased by 3.5-fold (range 2.2–6.3). Cmax increased by 2.3-fold (range 1.3–3.8).
Cyclosporine for oral use	AUC increased by 2.7-fold (range 1.5–4.7). Cmax increased by 1.8-fold (range 1.3–2.6).
Fluconazole	Not studied. Possible increase in everolimus concentration.
Diltiazem
Dronedarone	Not studied. Possible increase in everolimus concentration.
Ampranavir, fosamprenavir	Not studied. Possible increase in everolimus concentration.
Cannabidiol (P-gp inhibitor)	AUC ↑ by 2.5-fold Cmax ↑ by 2.5-fold
Grapefruit juice or other food products affecting CYP3A4/PgP	Not studied. Possible increase in everolimus concentration (effects may vary).		This combination should be avoided.
Potent and moderate inducers of CYP3A4
Rifampicin	AUC decreased by 63% (range 0–80%). Cmax decreased by 58% (range 10–70%).		Concomitant use of potent CYP3A4 inducers is not recommended. If a patient requires concomitant use of a potent CYP3A4 inducer, increasing the dose of the drug from 10 mg daily to 20 mg daily should be considered, increasing the dose by 5 mg on day 4 and day 8 after starting the inducer. This dose adjustment is expected to correct the AUC to the range observed without inducers. However, clinical data on such dose adjustment are lacking. If the use of the inducer is discontinued, the elimination period of the drug should be considered to be 3–5 days (a sufficient period for enzyme induction to subside significantly), and only after this period should the drug be resumed at the dose previously used before starting concomitant therapy.
Dexamethasone	Not studied. Possible decrease in concentration.
Antiepileptic agents (e.g., carbamazepine, phenobarbital, phenytoin)	Not studied. Possible decrease in concentration.
Efavirenz, nevirapine	Not studied. Possible decrease in concentration.
St. John’s wort (Hypericum perforatum)	Not studied. Possible significant decrease in concentration.		Products containing St. John’s wort should not be used during everolimus therapy.

Drugs whose plasma concentrations may be affected by everolimus.

Based on in vitro data, it is unlikely that systemic concentrations achieved after daily oral administration of the drug at a dose of 10 mg will lead to inhibition of PgP, CYP3A4, or CYP2D6. However, inhibition of intestinal CYP3A4 and PgP cannot be excluded. Interaction studies in healthy volunteers showed that co-administration of oral midazolam, a sensitive CYP3A substrate probe, with everolimus resulted in a 25% increase in midazolam Cmax and a 30% increase in AUC(0–inf). This effect is likely due to inhibition of intestinal CYP3A4 by everolimus. Therefore, everolimus may affect the bioavailability of drugs that are substrates of CYP3A4 and/or PgP when administered concomitantly. However, a clinically significant impact on systemic exposure to CYP3A4 substrates is not expected.

Concomitant administration of everolimus and depot octreotide increased octreotide Cmin, 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 was not established.

Concomitant administration of everolimus and exemestane increased exemestane Cmin and C2h by 45% and 64%, respectively. However, corresponding estradiol levels at steady state (4 weeks) did not differ between the two treatment groups. No increase in frequency of adverse reactions associated with exemestane use was observed in patients with hormone receptor-positive, progressive breast cancer receiving the combination therapy. The increase in exemestane levels is unlikely to affect efficacy or safety.

Concomitant use of angiotensin-converting enzyme (ACE) inhibitors.

Patients receiving concomitant ACE inhibitors (e.g., ramipril) have an increased risk of developing angioedema.

Vaccination.

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

Special precautions for use.

Non-infectious pneumonitis.

Non-infectious pneumonitis is a class effect of rapamycin derivatives, including Everonat. Non-infectious pneumonitis (including interstitial lung disease) has been observed in patients receiving everolimus, particularly in patients with advanced renal cell carcinoma (RCC). Some cases were severe, and fatal outcomes have rarely been reported. In patients presenting with non-specific respiratory symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom appropriate investigations have excluded infectious, neoplastic, or other non-medical causes, non-infectious pneumonitis should be considered. In patients with RCC, neuroendocrine tumors (NET), and hormone receptor-positive breast cancer, opportunistic infections such as Pneumocystis jirovecii (carinii) pneumonia (PJP/PCP) should be excluded from the differential diagnosis of non-infectious pneumonitis. Patients should be advised to promptly report any new or worsening respiratory symptoms.

Patients with radiological findings suggestive of non-infectious pneumonitis but with mild or no symptoms may continue treatment with Everonat 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 corticosteroid treatment for non-infectious pneumonitis, prophylaxis against PJP/PCP pneumonia may be considered.

Infections.

Everolimus has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including those caused by opportunistic microorganisms. In patients treated with everolimus, both localized and systemic infections have been observed, including pneumonia, other bacterial infections, invasive fungal infections such as aspergillosis, candidiasis, or PJP/PCP pneumonia, and viral infections, including reactivation of hepatitis B virus. Some of these infections were severe (e.g., leading to sepsis, including septic shock, respiratory or hepatic failure) and sometimes fatal.

Physicians and patients should be aware of the increased risk of infections during treatment with Everonat. Patients with active infections should receive appropriate therapy, and infections should be fully resolved prior to initiating Everonat treatment. Close monitoring for signs and symptoms of infection is recommended during treatment. In case of diagnosed infection, appropriate treatment should be initiated promptly, and treatment with Everonat should be interrupted or discontinued.

In cases of diagnosed invasive systemic fungal infection, Everonat should be discontinued immediately, and appropriate antifungal therapy should be initiated.

Cases of PJP/PCP pneumonia, sometimes with fatal outcomes, have been reported in patients receiving everolimus. The development of PJP/PCP may be associated with concomitant use of corticosteroids or other immunosuppressants. Prophylaxis against PJP/PCP may be necessary when concomitant use with corticosteroids or other immunosuppressants is required.

Hypersensitivity reactions.

Hypersensitivity reactions have been observed with everolimus, including symptoms such as anaphylaxis, dyspnea, flushing, hyperemia, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment).

Concomitant use with angiotensin-converting enzyme (ACE) inhibitors.

Patients concurrently taking an ACE inhibitor (e.g., ramipril) have an increased risk of developing angioedema (manifested as swelling of the airways or tongue, with or without respiratory impairment).

Stomatitis.

Stomatitis, including oral ulcers and oral mucositis, is the most common adverse reaction in patients receiving Everonat. Stomatitis typically occurs within the first 8 weeks of treatment. An uncontrolled study in postmenopausal women with breast cancer receiving everolimus and exemestane showed that a non-alcoholic corticosteroid oral solution used as a mouth rinse during the first 8 weeks of treatment may reduce the incidence and severity of stomatitis. Therefore, management of stomatitis may include prophylactic (in adults) and/or therapeutic use of locally applied medications, such as a non-alcoholic corticosteroid oral solution used as a mouth rinse. However, products containing alcohol, hydrogen peroxide, iodine, or thyme derivatives should not be used, as they may exacerbate the condition. Monitoring and treatment of fungal infections are recommended, particularly in patients receiving steroid medications. Antifungal agents should not be used prior to confirmation of a fungal infection diagnosis.

Renal impairment.

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

Laboratory tests and monitoring.

Renal function.

Elevations in serum creatinine levels, usually mild, have been reported in clinical trials. Renal function, including blood urea nitrogen (BUN), proteinuria, and serum creatinine, should be monitored before initiating Everonat and periodically thereafter.

Blood glucose levels.

Hyperglycemia has been reported in clinical trials. Fasting serum glucose levels should be monitored before starting Everonat and periodically thereafter. More frequent monitoring is recommended when Everonat is used concomitantly with other medicinal products that may cause hyperglycemia. Optimal glycemic control should be achieved, if possible, before initiating Everonat.

Blood lipid levels.

Dyslipidemia (including hypercholesterolemia and hypertriglyceridemia) has been reported. Cholesterol and triglyceride levels should be monitored before starting Everonat and periodically thereafter, and managed with appropriate medical therapy.

Hematological parameters.

Decreases in hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical trials. Complete blood counts should be monitored before starting Everonat and periodically thereafter.

Carcinoid tumors.

In a randomized, double-blind, multicenter study in patients with carcinoid tumors, everolimus plus octreotide-depot (Sandostatin® LAR®) was compared with placebo plus octreotide-depot. The study did not meet the primary efficacy endpoint (progression-free survival), and an interim analysis of overall survival numerically favored the placebo plus octreotide-depot group. Therefore, the safety and efficacy of everolimus in patients with carcinoid tumors have not been established.

Prognostic factors for gastrointestinal or lung neuroendocrine tumors.

In patients with non-functioning gastrointestinal or lung neuroendocrine tumors and favorable prognostic baseline factors (e.g., ileal primary tumor site, normal chromogranin A levels, or absence of bone marrow involvement), an individual benefit-risk assessment should be performed before initiating Everonat therapy. Limited evidence of benefit in progression-free survival was observed in the subgroup of patients with ileal primary tumors.

Interactions.

Concomitant use with inhibitors and inducers of CYP3A4 and/or the P-glycoprotein (PgP) efflux pump should be avoided. If concomitant use of a moderate CYP3A4 inducer and/or PgP inhibitor cannot be avoided, careful clinical monitoring is recommended. Dose adjustments may be based on predicted AUC (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use with strong CYP3A4/PgP inhibitors leads to a significant increase in everolimus plasma concentrations (see section "Interaction with other medicinal products and other forms of interaction"). There are currently insufficient data to recommend a dosing regimen in such cases. Therefore, concomitant use of Everonat with strong CYP3A4/PgP inhibitors is not recommended.

Everonat should be used with caution in combination with orally administered CYP3A4 substrates that have a narrow therapeutic index due to potential drug interactions. When Everonat is used concomitantly with orally administered CYP3A4 substrates with a narrow therapeutic index (e.g., pimozide, terfenadine, astemizole, cisapride, quinidine, ergot alkaloids, or carbamazepine), patients should be monitored for adverse events described in the product information for these CYP3A4 substrates.

Hepatic impairment.

Exposure to everolimus increases in patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment.

Everonat should be used in patients with severe hepatic impairment (Child-Pugh class C) only if the potential benefit outweighs the risk.

There are currently no clinical data on efficacy or safety that would allow dose adjustment recommendations to prevent adverse reactions in patients with hepatic impairment.

Vaccination.

Live vaccines should not be administered during treatment with Everonat.

Lactose.

This medicinal product is contraindicated in patients with rare hereditary conditions such as galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.

Wound healing complications.

Impaired wound healing is a known class effect of rapamycin derivatives, including Everonat. Therefore, Everonat should be used with caution during the perioperative period.

Use during pregnancy or breastfeeding.

Contraception.

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

Pregnancy.

There are insufficient data on the use of everolimus in pregnant women. 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, studies in animals have shown that everolimus and/or its metabolites are excreted in the milk of lactating rats. Therefore, women taking everolimus should not breastfeed during treatment and for 2 weeks after the last dose.

Fertility.

There are no data on the potential of everolimus to cause male or female infertility. However, amenorrhea (secondary amenorrhea and other menstrual cycle disturbances) and associated luteinizing hormone (LH)/follicle-stimulating hormone (FSH) imbalance have been observed in female patients. Based on preclinical data, there is a risk of impaired fertility in both men and women receiving everolimus.

Ability to drive and use machines.

Everonat has a minor or moderate influence on the ability to drive and operate machinery. If patients experience fatigue during treatment with Everonat, they should refrain from driving or operating machinery.

Method of Administration and Dosage

Treatment with Everonat should be initiated and carried out under the supervision of a physician experienced in anticancer therapy to ensure appropriate clinical monitoring of the medicinal product.

Dosage.

The recommended dose of Everonat is 10 mg once daily. Treatment should continue as long as clinical benefit is observed or until unacceptable toxicity occurs.

If a dose is missed, an additional dose should not be taken; instead, the next scheduled dose should be taken as usual.

Dose adjustments due to adverse reactions.

Dose modification may be required to manage severe adverse reactions and/or suspected intolerance. The dose of Everonat may be reduced or the drug temporarily discontinued. Dose adjustments are generally not required for grade 1 adverse reactions. If a dose reduction is necessary, a dose of 5 mg once daily is recommended, but not less.

Table 2 summarizes the recommendations for dose reduction, interruption, or discontinuation of everolimus due to adverse reactions. General recommendations for patient management are also provided. The treating physician's clinical judgment determines the management plan for each patient based on an individual benefit-risk assessment.

Dose adjustment of Everonat and recommendations for patient management
due to adverse reactions.

Table 2

Unfavorable reaction	Severity1	Dose adjustment of Afinitor and recommendations for patient management
Non-infectious pneumonitis	Grade 2	Consider temporarily discontinuing treatment until symptoms improve to ≤ Grade 1. Resume Afinitor at a dose of 5 mg once daily. Discontinue treatment if symptoms do not improve within 4 weeks.
	Grade 3	Withhold Afinitor until symptoms improve to ≤ Grade 1. Consider resuming Afinitor at a dose of 5 mg once daily. If Grade 3 toxicity recurs, consider discontinuing treatment.
	Grade 4	Discontinue Afinitor.
Stomatitis	Grade 2	Temporarily discontinue the drug until symptoms improve to ≤ Grade 1. Resume Afinitor at the same dose. If Grade 2 stomatitis recurs, discontinue the drug until symptoms improve to ≤ Grade 1. Resume Afinitor at a dose of 5 mg once daily.
	Grade 3	Temporarily discontinue the drug until symptoms improve to ≤ Grade 1. Resume Afinitor at a dose of 5 mg once daily.
	Grade 4	Discontinue Afinitor.
Other non-hematological toxicities (excluding metabolic disorders)	Grade 2	No dose adjustment is required for moderate toxicities. If toxicities worsen, temporarily discontinue the drug until symptoms improve to ≤ Grade 1. Resume Afinitor at the same dose. If Grade 2 toxicity recurs, discontinue Afinitor until symptoms improve to ≤ Grade 1. Resume treatment at a dose of 5 mg once daily.
	Grade 3	Temporarily discontinue the drug until symptoms improve to ≤ Grade 1. Consider resuming Afinitor at a dose of 5 mg once daily. If Grade 3 toxicity recurs, consider discontinuing treatment.
	Grade 4	Discontinue Afinitor.
Metabolic disorders (e.g., hyperglycemia, dyslipidemia)	Grade 2	No dose adjustment required.
	Grade 3	Temporarily discontinue the drug. Resume Afinitor at a dose of 5 mg once daily.
	Grade 4	Discontinue Afinitor.
Thrombocytopenia	Grade 2 (< 75, ≥ 50 × 109/l)	Temporarily discontinue the drug until symptoms improve to ≤ Grade 1 (≥ 75 × 109/l). Resume treatment at the same dose.
	Grade 3 and 4 (< 50 × 109/l)	Temporarily discontinue the drug until symptoms improve to ≤ Grade 1 (≥ 75 × 109/l). Resume Afinitor at a dose of 5 mg once daily.
Neutropenia	Grade 2 (≥ 1 × 109/l)	No dose adjustment required.
	Grade 3 (< 1, ≥ 0.5 × 109/l)	Temporarily discontinue the drug until symptoms improve to ≤ Grade 2 (≥ 1 × 109/l). Resume treatment at the same dose.
	Grade 4 (< 0.5 × 109/l)	Temporarily discontinue the drug until symptoms improve to ≤ Grade 2 (≥ 1 × 109/l). Resume Afinitor at a dose of 5 mg once daily.
Febrile neutropenia	Grade 3	Temporarily discontinue the drug until symptoms improve to ≤ Grade 2 (≥ 1.25 × 109/l) and fever resolves. Resume Afinitor at a dose of 5 mg once daily.
	Grade 4	Discontinue Afinitor.
1Severity levels correspond to the National Cancer Institute (US NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.

Special populations.

Elderly patients.

Dose adjustment is not required.

Renal impairment.

Dose adjustment is not required.

Hepatic impairment.

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

Dosage adjustment should be performed if there are changes in hepatic function (according to the Child-Pugh classification) during treatment.

Method of administration.

Everonat should be administered orally once daily at the same time each day, regardless of food intake. Tablets should be swallowed whole with a glass of water. Tablets must not be chewed or crushed.

Children.

The safety and efficacy of Everonat in children (under 18 years of age) have not been established. Currently, no information is available.

Overdose.

Human experience with overdose is very limited. In adult patients, single doses up to 70 mg resulted in a manageable acute tolerability profile. In all cases of overdose, general supportive measures should be initiated.

Adverse Reactions

Patients with RCC, NET, and HR-positive breast cancer

The safety profile was established based on pooled data from 2879 patients who received everolimus for indications of RCC, NET, and HR-positive breast cancer across 11 clinical studies, 5 of which were randomized, double-blind, placebo-controlled Phase III trials, and 6 were open-label Phase I and Phase II studies.

According to the pooled safety data, the most common adverse reactions (incidence ≥ 1/10) were, in decreasing order: stomatitis, rash, fatigue, diarrhea, infections, nausea, decreased appetite, anemia, altered taste, pneumonitis, peripheral edema, hyperglycemia, asthenia, pruritus, weight loss, hypercholesterolemia, epistaxis, cough, and headache.

The most common adverse reactions of Grade 3–4 severity (incidence ≥ 1/100 and < 1/10) were stomatitis, anemia, hyperglycemia, infections, fatigue, diarrhea, pneumonitis, asthenia, thrombocytopenia, neutropenia, dyspnea, proteinuria, lymphopenia, bleeding, hypophosphatemia, rash, arterial hypertension, pneumonia, increased aspartate aminotransferase (AST) levels, increased alanine aminotransferase (ALT) levels, and diabetes mellitus. Severity grades were defined according to CTCAE versions 3.0 and 4.03.

Table 3 presents data covering adverse reactions observed with the highest frequency in clinical studies among patients receiving everolimus 10 mg/day compared to patients receiving placebo. Table 5 presents data covering adverse reactions by number of cases based on pooled data from patients receiving everolimus in three RCTs (including both double-blind and the open-label extension study). Adverse reactions in Tables 4 and 5 are listed by MedDRA system organ class and frequency of occurrence. Frequency categories are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data). Within each frequency group, adverse reactions are listed in decreasing order of severity.

Table 3

Infections and infestations
Very common	Infectionsa*
Blood and lymphatic system disorders
Very common	Anaemia
Common	Thrombocytopenia, neutropenia, leukopenia, lymphopenia
Uncommon	Pancytopenia
Rare	True erythrocytic aplasia
Immune system disorders
Uncommon	Hypersensitivity
Metabolism and nutrition disorders
Very common	Decreased appetite, hyperglycaemia, hypercholesterolaemia
Common	Hypertriglyceridaemia, hypophosphataemia, diabetes mellitus, hyperlipidaemia, hypokalaemia, dehydration, hypocalcaemia
Psychiatric disorders
Common	Insomnia
Nervous system disorders
Very common	Disturbance of taste, headache
Uncommon	Aggression
Eye disorders
Common	Periorbital oedema
Uncommon	Conjunctivitis
Cardiac disorders
Uncommon	Heart failure
Vascular disorders
Common	Bleedingb, arterial hypertension
Uncommon	Flushing, deep vein thrombosis
Respiratory, thoracic and mediastinal disorders
Very common	Pneumonitisc, epistaxis, cough
Common	Dyspnoea
Uncommon	Haemoptysis, pulmonary embolism
Rare	Acute respiratory distress syndrome
Gastrointestinal disorders
Very common	Stomatitisd, diarrhoea, nausea
Common	Vomiting, dry mouth, abdominal pain, mucosal inflammation, oral and pharyngeal pain, dyspepsia, dysphagia
Hepatic disorders
Common	Elevated levels of alanine aminotransferase and aspartate aminotransferase
Skin and subcutaneous tissue disorders
Very common	Rash, pruritus
Common	Dry skin, nail disorders, mild alopecia, acne, erythema, onycholysis, palmar-plantar erythrodysesthesia syndrome, skin exfoliation, skin disorders
Rare	Angioedema*
Bone and connective tissue disorders
Common	Joint pain
Renal and urinary disorders
Common	Proteinuria*, increased creatinine levels, renal failure*
Uncommon	Increased daytime urinary frequency, acute renal failure*
Reproductive system and breast disorders
Common	Irregular menstruatione
Uncommon	Amenorrhoeae*
General disorders
Very common	Fatigue, asthenia, peripheral oedema
Common	Chills
Uncommon	Non-cardiac chest pain, impaired wound healing
Investigations
Very common	Weight decreased
*See also section "Description of selected adverse reactions". aIncludes (common) pneumonia, urinary tract infections; (uncommon) bronchitis, herpes zoster, sepsis, abscess and isolated cases of opportunistic infections [e.g. aspergillosis, candidiasis, Pneumocystis pneumonia PJP/PCP and hepatitis B (see section "Special warnings and precautions for use")] and (rare) viral myocarditis. bIncludes various cases of bleeding from different sites not specified separately. cIncludes (very common) pneumonitis, (common) interstitial lung disease, pulmonary infiltrates and (rare) pulmonary alveolar haemorrhage, pulmonary toxicity and alveolitis. dIncludes (very common) stomatitis, (common) aphthous stomatitis, oral and lingual mucosal ulceration and (uncommon) gingival pain, glossitis, glossodynia. eFrequency based on number of women aged 10 to 55 years included in pooled data.

Description of individual adverse reactions.

The use of everolimus in clinical trials resulted in serious cases of hepatitis B virus reactivation, including fatal cases. Reactivation of infection is an expected phenomenon during periods of immunosuppression.

During clinical trials and in post-marketing spontaneous reports, the use of everolimus has been associated with cases of renal failure (including fatal cases), proteinuria, and elevated serum creatinine levels. Monitoring of renal function is recommended.

Based on data from clinical trials and spontaneous post-marketing reports, the use of everolimus has been associated with cases of amenorrhea (secondary amenorrhea and other menstrual cycle disorders).

Based on data from clinical trials and spontaneous post-marketing surveillance reports, the use of everolimus has been linked to cases of PJP/PCP pneumonia, sometimes with fatal outcomes.

Based on data from clinical trials and spontaneous post-marketing reports, cases of angioedema have occurred both with concomitant use of ACE inhibitors and without it.

Elderly patients.

In the combined safety-evaluable population, 37% of patients receiving everolimus were aged ≥65 years. The frequency of adverse reactions leading to treatment discontinuation was higher in patients aged ≥65 years (20% vs. 13%). The most common adverse reactions leading to treatment discontinuation were pneumonitis (including interstitial lung disease), stomatitis, fatigue, and dyspnea.

Reporting of suspected adverse reactions.

Reporting of suspected adverse reactions after drug registration is of great importance. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report all suspected adverse reactions through the national reporting system.

Shelf life. 2 years.

Storage conditions. Store at temperatures not exceeding 30 °C. Store in the original packaging to protect from light and moisture. Keep out of reach of children.

Packaging. 7 tablets per blister, 4 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. Natco Pharma Limited.

Manufacturer's address and location of operations.

Pharma Division, Kothur, Rangareddy, Telangana 509228, India.