Everolimus-vista

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT EVEROLIMUS-VISTA (EVEROLIMUS-VISTA)

Composition:

Active substance: everolimus;

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

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

Pharmaceutical form. Tablets.

Main physicochemical properties: oval, biconvex tablets, white to almost white in color;

2.5 mg: tablets with imprint E9VS on one side and 2.5 on the other side;

5 mg: tablets with imprint E9VS 5 on one side;

10 mg: tablets with imprint E9VS 10 on one side.

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 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 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 activation function of the estrogen receptor, which mediates 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 levels. 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 in vitro and in vivo.

Pharmacokinetics.

Absorption.

In patients with advanced solid tumors, maximum everolimus concentration (Cmax) is reached at a median time of 1 hour after daily administration of 5 mg or 10 mg everolimus taken 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.

Relative bioavailability/bioequivalence

In a relative bioavailability study, AUC0–inf after administration of 5 × 1 mg everolimus tablets as an aqueous suspension was equivalent to that after administration of intact 5 × 1 mg everolimus tablets. Cmax after administration of 5 × 1 mg everolimus tablets as a suspension was 72% of that after administration of intact 5 × 1 mg everolimus tablets.

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 in plasma constitutes approximately 20% of the total blood concentration observed in cancer patients receiving 10 mg everolimus daily. 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 central compartment and 517 L for the peripheral compartment.

Metabolism.

Everolimus is a substrate of CYP3A4 and P-glycoprotein (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 an everolimus phosphatidylcholine conjugate. These metabolites were also detected in animals used in toxicity studies. The activity of these metabolites was approximately 100-fold lower than that of everolimus. Therefore, everolimus is primarily responsible for the overall pharmacological activity.

Elimination.

The mean CL/F of 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 excretion studies in oncology patients have not been conducted, but 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 in the daily dose range of 5 to 10 mg. Steady state was achieved within 2 weeks. Cmax was dose-proportional in the range of 5 to 10 mg. tmax occurred 1–2 hours after dosing. AUC0–τ and trough concentration (Cmin) prior to dosing were highly correlated.

Special patient groups.

Hepatic impairment.

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

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

In the second study involving 34 subjects with varying degrees of hepatic impairment, everolimus 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. Pharmacokinetic modeling results after multiple dosing support dose adjustment 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 everolimus CL/F 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 evaluations 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 African-American transplant patients 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 nonsteroidal aromatase inhibitors has resulted in recurrence or progression.
• Treatment of patients with advanced renal cell carcinoma in whom the disease progresses during or after VEGF-targeted therapy (targeting vascular endothelial growth factor).
• Treatment of unresectable or metastatic, well or moderately differentiated pancreatic neuroendocrine tumors in adult patients with progressive disease.
• Treatment of patients with neuroendocrine tumors of gastrointestinal tract or lungs. The medicinal product EVEROLIMUS-VISTA is indicated for the treatment of unresectable or metastatic, well-differentiated (grade 1 or grade 2) non-functioning neuroendocrine tumors of the gastrointestinal tract or lungs in adults with progressive disease.

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

Everolimus is a substrate of CYP3A4 as well as 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.

CYP3A4 and PgP inhibitors 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.

CYP3A4 and PgP inducers 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.

Table 1

Effect of other active substances on everolimus

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 everolimus with 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 is advised. If a patient requires concomitant use of a moderate CYP3A4 or PgP inhibitor, dose reduction of everolimus 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, and dose adjustment of everolimus may be necessary as needed (see sections "Special precautions" and "Dosage and administration"). If the moderate inhibitor is discontinued, consider that the drug elimination period is at least 2–3 days (the average elimination time for most moderate inhibitors used), and only after this period should everolimus be resumed at the dose previously used before initiation of 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).
Oral cyclosporine	AUC increased by 2.7-fold (range 1.5–4.7). Cmax increased by 1.8-fold (range 1.3–2.6).
Cannabidiol (PgP inhibitor)	AUC increased by 2.5-fold. Cmax increased by 2.5-fold.
Fluconazole	Not studied. An increase in everolimus concentration is possible.
Diltiazem
Dronedarone	Not studied. An increase in everolimus concentration is possible.
Amprinavir, fosamprenavir	Not studied. An increase in everolimus concentration is possible.
Grapefruit juice or other food products affecting CYP3A4/PgP	Not studied. An increase in everolimus concentration is possible (the magnitude of effect may vary).	This combination should be avoided.
Potent and moderate inducers of CYP3A4
Rifampicin	AUC decreased by 3% (range 0–80%). Cmax decreased by 58% (range 10–70%).	Concomitant use with potent CYP3A4 inducers is not recommended. If a patient requires concomitant use of a potent CYP3A4 inducer, consider increasing the dose from 10 mg daily to 20 mg daily, escalating the dose by 5 mg on day 4 and day 8 after starting the inducer. This dose adjustment is expected to maintain AUC within the range observed in the absence of inducers. However, clinical data on such dose adjustment are lacking. If the inducer is discontinued, consider that the elimination period is 3–5 days (sufficient time for enzyme induction to subside significantly), and only after this period should the previous dose of everolimus be resumed.
Dexamethasone	Not studied. A decrease in concentration is possible.
Antiepileptic agents (e.g., carbamazepine, phenobarbital, phenytoin)	Not studied. A decrease in concentration is possible.
efavirenz, nevirapine	Not studied. A decrease in concentration is possible.
St. John's wort (Hypericum perforatum)	Not studied. A significant decrease in concentration is possible.	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 results, 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, 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 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 bioavailability when administered concomitantly with drugs that are substrates of CYP3A4 and/or PgP. However, a clinically significant effect on exposure to systemically administered 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 could not be established.

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

Concomitant use of angiotensin-converting enzyme (ACE) inhibitors
Patients who concomitantly use an ACE inhibitor (e.g., ramipril) have an increased risk of developing angioedema.

Vaccination

Immune response to vaccines may be altered; therefore, vaccine efficacy 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, and rubella (MMR) vaccine, oral polio vaccine, BCG (Bacillus Calmette–Guérin), yellow fever vaccine, varicella vaccine, and typhoid vaccine TY21a.

Radiation therapy

Enhanced toxic effects of radiation therapy have been reported in patients receiving everolimus (see sections «Special precautions» and «Adverse reactions»).

Special precautions.

Non-infectious pneumonitis.

Non-infectious pneumonitis is a class-effect of rapamycin derivatives, including everolimus. 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 been reported rarely. In patients presenting with non-specific respiratory symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, or other non-medical causes have been excluded by appropriate investigations, non-infectious pneumonitis should be considered. In patients with RCC, neuroendocrine tumors (NET), or 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 who have radiological findings suggestive of non-infectious pneumonitis but are asymptomatic or have only mild symptoms may continue treatment with everolimus 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 pneumonia (PJP/PCP) may be advisable.

Infections.

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

Physicians and patients should remain vigilant for increased risk of infections during everolimus therapy. Patients with active infections should receive appropriate treatment, and infections should be fully resolved prior to initiating everolimus. Close monitoring for signs and symptoms of infection is recommended during treatment. If an infection is diagnosed, appropriate therapy should be initiated promptly, and interruption or discontinuation of everolimus should be considered. In cases of invasive systemic fungal infection, everolimus should be discontinued immediately, and appropriate antifungal therapy initiated.

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

Hypersensitivity reactions.

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

Concomitant use with 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 everolimus. 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 mouthwash 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 topical agents such as a non-alcoholic corticosteroid oral solution used as a mouthwash. However, agents containing alcohol, hydrogen peroxide, iodine, or thyme derivatives should be avoided, as they may exacerbate symptoms. Fungal infections should be monitored and treated, particularly in patients receiving steroid therapy. Antifungal agents should not be used before a diagnosis of fungal infection is established.

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

Blood glucose levels.

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

Blood lipid levels.

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

Hematological parameters.

Decreases in hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical trials. Complete blood counts should be monitored before starting everolimus 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 its 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 everolimus 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 or inducers of CYP3A4 and/or P-glycoprotein (PgP) efflux pump should be avoided. If concomitant use of moderate CYP3A4 and/or PgP inhibitors or inducers cannot be avoided, careful clinical monitoring is required. The dose of everolimus should be adjusted based on predicted AUC. Concomitant use with strong CYP3A4/PgP inhibitors significantly increases everolimus plasma concentrations. There are insufficient data to recommend a specific dosing regimen in such cases; therefore, concomitant use of everolimus with strong CYP3A4 inhibitors is not recommended.

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

Hepatic impairment.

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

Everolimus should be used in patients with severe hepatic impairment (Child-Pugh Class C) only if the potential benefit outweighs the risk. There are no clinical data on efficacy or safety to support dose adjustment to prevent adverse reactions in patients with hepatic impairment.

Vaccination.

Live vaccines should not be administered during treatment with everolimus.

Wound healing complications.

Impaired wound healing is a known 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 (including radiation esophagitis, radiation pneumonitis, and radiation dermatitis), including fatal cases, have been reported when everolimus was administered during or shortly after radiation therapy. Caution is warranted regarding potential enhancement of radiation toxicity in patients receiving everolimus in close temporal proximity to radiation therapy. Radiation recall reactions have also been reported in patients who received everolimus after prior radiation therapy. If radiation recall syndrome occurs, interruption or discontinuation of everolimus should be considered.

Important information on excipients.

Lactose.

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

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 the last dose. 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 receiving 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 disorders) and associated luteinizing hormone (LH)/follicle-stimulating hormone (FSH) imbalance have been observed in female patients receiving everolimus. Preclinical data indicate a risk of impaired fertility in both men and women treated with everolimus.

Effects on ability to drive and use machines.

Everolimus has minor or moderate influence on the ability to drive and use machines. Patients experiencing fatigue during treatment should refrain from driving or operating machinery.

Method of administration and dosage.

Everolimus treatment should be initiated and conducted under the supervision of a physician experienced in the use of anticancer therapies, in order to ensure appropriate clinical monitoring of the medicinal product.

Dosage.

The recommended dose of everolimus is 10 mg once daily. Treatment should continue for as long as clinical benefit is observed or until unacceptable toxicities occur. If a dose is missed, an additional dose should not be taken; however, the next scheduled dose should be taken at the usual time. Dosage adjustments in response to adverse reactions.

Dose modification or temporary interruption of everolimus may be required to manage severe adverse reactions and/or suspected intolerance. Dose reduction or temporary discontinuation of the drug may be necessary. Dose adjustments are generally not required for grade 1 adverse reactions. If dose reduction is needed, a daily dose of 5 mg is recommended, but not less.

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

Table 2

Everolimus dose adjustment and patient management recommendations in response to adverse reactions

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

Special populations.

Geriatric 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): everolimus should be used only if the anticipated benefit outweighs the risk. In such cases, the dose should not exceed 2.5 mg once daily.

Dose adjustment should be performed if there is a change in hepatic function (according to Child-Pugh classification) during treatment.

Method of administration.

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

Pediatric population.

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

Overdose.

Experience with overdose in humans is very limited.

Symptoms. In the adult population, single doses up to 70 mg resulted in a tolerable acute tolerability profile.

Treatment. 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 is based on combined data from 2879 patients who received everolimus for indications of RCC, NET, and HR-positive breast cancer in 11 clinical studies, including 5 randomized, double-blind, placebo-controlled Phase III trials and 6 open-label Phase I and Phase II trials.

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

The most commonly reported 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, hemorrhage, 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 at the highest frequency during clinical trials in patients treated with 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 who received everolimus in three TSC trials (including both double-blind and one open-label extension trial). In Tables 4 and 5, adverse reactions are listed by MedDRA system organ class and frequency categories. Frequency categories are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data). Within each frequency category, adverse reactions are listed in order of decreasing severity.

Table 3

Infections and infestations
Very common	Infectionsa*
Blood and lymphatic system disorders
Very common	Anemia
Common	Thrombocytopenia, neutropenia, leukopenia, lymphopenia
Uncommon	Pancytopenia
Rare	True erythrocyte 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	Taste disturbance, headache
Uncommon	Aggression
Eye disorders
Common	Periorbital edema
Uncommon	Conjunctivitis
Cardiac disorders
Uncommon	Heart failure
Vascular disorders
Common	Bleedingb, arterial hypertension, lymphedemag
Uncommon	Flushing, 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 and pharyngeal pain, dyspepsia, dysphagia
Hepatobiliary disorders
Common	Elevated ALT and AST levels
Skin and subcutaneous tissue disorders
Very common	Rash, pruritus
Common	Dry skin, nail disorders, mild alopecia, acne, erythema, onycholysis, hand-foot erythrodysesthesia syndrome, skin exfoliation, skin disorders
Rare	Angioneurotic edema*
Musculoskeletal 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	Amenorrheae*
General disorders
Very common	Fatigue, asthenia, peripheral edema
Common	Chills
Uncommon	Non-cardiac chest pain, impaired wound healing
Investigations
Very common	Weight decreased
Injury, poisoning and procedural complications
Frequency unknownf	Radiation recall syndrome
* See also section "Description of selected adverse reactions". a Includes (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 precautions for use")] and (rare) viral myocarditis. b Includes various cases of bleeding from different sites not specified separately. c Includes (very common) pneumonitis, (common) interstitial lung disease, pulmonary infiltrates, and (rare) pulmonary alveolar hemorrhage, pulmonary toxicity, and alveolitis. d Includes (very common) stomatitis, (common) aphthous stomatitis, oral mucosal ulceration, and tongue ulceration, and (uncommon) gingival pain, glossitis, glossodynia. e Frequency based on number of women aged 10 to 55 years reported in pooled data. f Information on adverse reaction obtained from post-marketing studies. g Information on adverse reaction obtained from post-marketing reports. Frequency was determined based on combined safety data from oncology trials.

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 outcomes), proteinuria, and increased serum creatinine concentration. Monitoring of renal function is recommended.

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

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

Elderly patients

In the combined safety 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 suspected adverse reactions

Reporting of suspected adverse reactions after drug registration is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Store in the original packaging to protect from light. Keep out of reach of children.

Packaging. 5 tablets in a blister, 6 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Sicor España, S.L.

Manufacturer's address and location of its business operations.

C/Castello, no1, Sant Boi de Llobregat, Barcelona, 08830, Spain.