Athlete - instructions for use, dose, side effects, contraindications

Active substanceEverolimusEverolimus

Similar drugsTo uncover

Athenitor®

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Novartis Pharma AG Switzerland

Athenitor®

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Novartis Pharma AG Switzerland

Athenitor®

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Novartis Pharma AG Switzerland

Sertican®

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Novartis Pharma AG Switzerland

Sertikan

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Novartis Pharma AG Switzerland

Dosage form: & nbsppills

Composition:1 tablet contains: active substance - everolimus 5 mg and 10 mg; Excipients: lactose anhydrous 143.75 mg and 287.50 mg, crospovidomas 50.00 mg and 100.00 mg, hypromellose 45.00 mg and 90.00 mg, lactose monohydrate 4.90 mg and 9.80 mg, magnesium stearate 1.25 mg and 2.50 mg, butyl hydroxytoluene 0.10 mg and 0.20 mg.

Description:Tablets 5 mg: oblong pills with a bevel, from white to white with a yellowish hue of color, with an embossed "NVR" on one side and "5" on the other.
Tablets 10 mg: oblong tablets with a bevel, from white to white with a yellowish shade of color, with an embossed "NVR" on one side and "UHE" on the other.

Pharmacotherapeutic group:antitumor agent, protein kinase inhibitor

ATX: & nbsp

L.04.A.A.18 Everolimus

Pharmacodynamics:The active substance of the preparation of Atfinitor®, everolimus, is an inhibitor of proliferative signal transmission.
Everolimus is a selective inhibitor of serine-threonine kinase mTOR (mammalian rapamycin target) specifically affecting the mTORCl complex of signal-converting mTOR kinase and regulatory regulatory protein of mTOR.The mTORCl complex is the most important regulator of protein synthesis in the distal part of the PI3K / AKT-dependent cascade, the regulation of which is disturbed in most human malignant tumors. Everolimus shows its activity due to its high affinity interaction with intracellular receptor protein FKBP12. Complex RKBR12-everolimus binds to mTORCl, inhibiting its ability to transmit signals.
The mTORCl signal function is realized through modulation of the phosphorylation of distal effector cells, of which the most fully characterized translation regulators are the S6 (S6K1) ribosomal protein kinase and the eukaryotic cell initiation factor, the 4E-binding protein (4E-BP1). The disruption of the function of S6K1 and 4E-BP1 due to inhibition of mTORCl disrupts the translation of the encoded mRNAs of the major proteins involved in the regulation of the cell cycle, glycolysis, and cell adaptation to low oxygen levels (hypoxia). This suppresses tumor growth and the expression of hypoxia-induced factors (eg transcription factor HIF-1). The latter leads to a decrease in the expression of factors that enhance the processes of angiogenesis in the tumor (eg, vascular endothelial growth factor - VEGF). The signal transmission through mTORCl is regulated by the genes-suppressors of tumor growth: Tuberous Sclerosis 1 and 2 genes (TSC1, TSC2). In tuberous sclerosis, a genetically determined disease, inactivating mutations in one or both TSC1 and TSC2 genes lead to the formation of multiple hamartomas of different localizations.
Everolimus is an active inhibitor of the growth and proliferation of tumor cells, endothelial cells, fibroblasts and smooth muscle cells of blood vessels.
Everolimus reliably reduced the risk of progression of the disease and death of patients with advanced and / or metastatic renal cell carcinoma after progression in anti-angiogenic therapy by 67%, and the disease-free survival was 4.9 months.
Within 6 months, 36% of patients who received everolimus, there was no progression of the disease. The use of everolimus can significantly improve the quality of life of patients (the impact of the symptoms of the disease on various areas of the patient's life was assessed).
With the use of everolimus in patients with advanced and / or metastatic neuroendocrine tumors, the progression-free survival rate for 18 months was 34.2%.
Activation of the mTOR signaling pathway is the key adaptive mechanism of the development of resistance to endocrine therapy in patients with breast cancer.
Different ways of signal transmission are activated when developing resistance to endocrine therapy. The main one is the PI3K / AKT / mTOR pathway, which is activated in breast cancer cells that are primarily resistant or have lost sensitivity to endocrine therapy with aromatase inhibitors or antiestrogen drugs.
The mTOR inhibitor everolimus (RAD001) in breast cancer with activation of the PI3K / AKT / mTOR pathway can restore the tumor's sensitivity to endocrine therapy. In in vitro studies have shown that the hormone-HER2 and tumor cells + breast cancer sensitive to the inhibitory effects of everolimus and antitumor activity of the combination therapy everolimus and an aromatase inhibitor, ACP or HER2 exceeds that provided by each component alone. Combined therapy with everolimus and aromatase inhibitor allows to increase the progression-free survival 2.6 times and, respectively, 64% to reduce the likelihood of disease progression and death.
The administration of everolimus to patients with kidney / kidney angiomyolipoma associated with tuberous sclerosis leads to a statistically significant decrease in neoplasm volume and a delayed progression of angiomyolipoma.

Pharmacokinetics:

Suction

Maximum concentration (FROM_max) everolimus in the blood after taking the drug inside at doses of 5 to 70 mg (fasting or with a small amount of low-fat food) is achieved after 1-2 hours. FROM_max with a daily intake of the drug varies proportionally to the dose in the range of 5 to 10 mg. When taking a single dose of everolimus 20 mg and higher, the increase FROM_max occurs less than proportionally to the dose, but the area under the concentration-time curve (AUC) increases in proportion to the dose when taken from 5 mg to 70 mg of the drug.

When taking everolimus at a dose of 10 mg in the form of tablets with foods high in fat AUC and FROM_max of the drug decreased by 22% and 54%, respectively. Simultaneous intake of food with a low fat content reduced the AUC and FROM_max by 32% and 42%, respectively. In healthy volunteers who received 9 mg everolimus once (in the form of three dispersible tablets at a dosage of 3 mg) when taken with high and low fat food, the everolimus AUC decreased by 11.7% and 29.5%respectively, with decreasing FROM_max by 59.8% and 50.2%, respectively. However, eating did not have a significant effect on the elimination of the drug within 24 hours (for both dosage forms).

Distribution

The percentage of everolimus concentration in blood and blood plasma, which is dependent on the concentration of the compound in the range of 5 to 5000 ng / ml, varies from 17% to 73%. Number of everolimus in plasma is approximately 20% of its concentration in whole blood at concentrations of substances detected in the blood of cancer patients receiving everolimus at 10 mg per day. The connection with plasma proteins is approximately 74% in healthy volunteers and in patients with impaired liver function of moderate severity.

In experimental studies, it was shown that, after intravenous administration, the penetration of everolimus across the blood-brain barrier depends on the dose non-linearly, suggesting saturation of the blood-brain barrier pump, which ensures that the drug enters the brain tissue from the blood. Penetration of everolimus through the blood-brain barrier was also demonstrated in animals receiving the drug inside.

Metabolism

Everolimus is a substrate for the isoenzyme CYP3A4 and P-glycoprotein (P-GP). After taking the drug inside the blood everolimus circulates basically unchanged. Six major metabolites of everolimus, represented by three monohydroxylated metabolites, two open-ring hydrolytic conversion products and an everolimus phosphatidylcholine conjugate are identified in human blood. These metabolites were inferior to Everolimus by a factor of about 100. Therefore, it is generally accepted that most of the overall pharmacological activity of everolimus is due to the action of the unaltered compound.

Excretion

After the administration of a single dose of radio-labeled everolimus, most (80%) of the radioactivity was detected in the feces, a small amount (5%) was excreted by the kidneys. The unchanged substance was not determined either in urine or in feces.

Pharmacokinetics in an equilibrium state

After a daily intake of everolimus, the AUC_0-_τ were proportional to the dose of the drug when used in doses of 5 to 10 mg per day. The equilibrium state was reached within two weeks. FROM_maxeverolimus was proportional to the dose when the drug was administered in doses of 5 to 10 mg per day. Time to reach the maximum concentration in the blood plasma (T_max) was 1-2 hours.

With the daily administration of everolimus upon reaching the equilibrium state, there was a significant correlation between AUC_0-_τ and the concentration of the drug in the blood before taking the next dose. The half-life of everolimus is about 30 hours.

Pharmacokinetics in selected patient groups

Patients with impaired hepatic function

With the use of everolimus in patients with impaired liver function, the systemic effect of the drug increases in 1.6, 2.0-3.3 and 3.6 times, respectively, with mild hepatic insufficiency (class A according to Child-Pugh classification), medium degree Gravity (class B according to the Child-Pugh classification) and severe degree (Child-Pugh class C). It is necessary to correct the dose of everolimus in case of a violation of the liver function (see "Method of administration and dose").

Patients with impaired renal function

There was no significant effect of creatinine clearance (from 25 to 178 ml / min) on the clearance (CL / F) of everolimus in patients with progressive solid tumors.Post-transplantation disorders of kidney function (creatinine clearance from 11 to 107 ml / min) did not affect the pharmacokinetics of everolimus in patients after organ transplantation.

Patients aged ≤18 years

The use of everolimus in children and adolescents up to 18 years according to indications: common and / or metastatic renal cell carcinoma and the common and / or metastatic neuroendocrine tumors of the gastrointestinal tract, lung and pancreatic cancer, hormone-dependent advanced breast cancer, angiomyolipoma of kidney associated with tuberous sclerosis in the absence of SEGA, is contraindicated.

Patients ≥65 years of age

Significant influence of the age of patients (from 27 to 85 years) on the clearance of everolimus (CL / F from 4.8 to 54.7 l / h) after taking the drug inside was not detected.

Impact of race

The clearance of everolimus (CL / F) after ingestion inside the face of Caucasoid and Mongoloid races with a similar function of the liver does not differ.

According to the population pharmacokinetic analysis in the Negroid race after organ transplantation, the everolimus clearance (CL / F) (after ingestion) was on average 20% higher than in Caucasians.

Effect of exposure on efficiency

There was some correlation between a decrease in 4E-BP1 phosphorylation in tumor tissue and C_min everolimus in the blood in a steady state (equilibrium) state after a daily intake of 5 or 10 mg of the drug.

Additional data suggest that a decrease in phosphorylation of S6 kinase is very sensitive to inhibition of mTOR under the influence of everolimus. The suppression of phosphorylation of the translation initiation factor eIF-4G was complete for all valuesC_min Everolimus, determined in the blood with a daily intake of the drug at a dose of 10 mg.

Indications:

Common and / or metastatic renal cell carcinoma with inefficiency of anti-angiogenic therapy.

Common and / or metastatic neuroendocrine tumors of the gastrointestinal tract, lung and pancreas.

Hormone-dependent common breast cancer in postmenopausal women in combination with an aromatase inhibitor after previous endocrine therapy.

Angiomyolipoma of the kidney, not requiring immediate surgical intervention, in patients with tuberous sclerosis.

Contraindications:Hypersensitivity to everolimus, other derivatives of rapamycin or any of the auxiliary components of the drug.
-Pregnancy and the period of lactation.
-Children's age and adolescence under 18 years.
It is not recommended for patients with rare hereditary diseases, such as lactase deficiency, lactose intolerance, glucose-galactosia malabsorption, since the dosage form contains lactose.
It is not recommended simultaneous use with potent inhibitors of the isoenzyme CYP3A4 and / or P-GP.
It is not recommended to use simultaneously with powerful inductors CYP3A4 isoenzyme or P-glycoprotein inducers (P-GP pump).

Carefully:

Caution should be exercised while using everolimus with moderate inhibitors of CYP3A4 or inhibitors of P-GP.

Everolimus should not be used in patients with severe liver failure (class C according to Child-Pyo classification), unless the benefits of taking the drug exceed the possible risk.
Since the use of derivatives of rapamycin, including the preparation of the Athenter® The process of wound healing can be slowed down, care should be taken when using the drug in patients before surgical interventions.

Pregnancy and lactation:The drug Atinitor® is contraindicated for use during pregnancy and breastfeeding.
During therapy with the drug Afinitor® and a minimum of 8 weeks after completion of therapy for patients of childbearing age, reliable methods of contraception should be used.
Fertility
No data on the effect of the drug® on fertility of men and women, however, based on the results of preclinical studies, it can be concluded that the therapy with the drug Afinitor® can negatively affect the fertility of men and women.

Dosing and Administration:Treatment with the drug Afinitor® should be done only under the supervision of a doctor who has experience working with antitumor drugs or treating patients with tuberous sclerosis.
The drug Athenitor ® should be taken orally once a day at the same time (preferably in the morning) on an empty stomach or after taking a small amount of food that does not contain fat. Tablets should be swallowed whole, washed down with a glass of water, they can not be chewed or crushed. Treatment with the drug is carried out as long as the clinical effect remains and there are no signs of intolerable toxicity.
Common and / or metastatic renal cell carcinoma with ineffective antiangiogenic therapy: common and / or metastatic neuroendocrine tumors of the gastrointestinal tract, lung and pancreas,hormone-dependent common breast cancer, angiomyolipoma of the kidney, not requiring immediate surgical intervention, in patients with tuberous sclerosis.
The recommended dose of the drug Afinitor® is 10 mg once a day.
Recommendations for changing the dose of the drug Afinitor® in the development of adverse events
Correction of severe and / or intolerable adverse events (AEs) may require temporary discontinuation of therapy with or without a dose reduction. If a dose reduction is required, a dose of approximately 50% less than the previous dose is recommended.
Table 1 shows the recommendations for changing the dose of the drug in the development of AE. The management of the patient should be based on an individual assessment of the benefits and risks, taking into account the characteristics of each patient.
Table 1. Recommendations for changing the dose of the drug Afinitor® in the development of adverse events

Unwanted reaction	Degree of severity1	Recommendations for dose modification and correction of adverse events2
Noninfectious pneumonitis	Degree 1 Absence of symptoms, except for radiographic signs	Correction of the dose is not required. Condition monitoring.
	Degree 2 Symptoms that do not affect daily life	The termination of therapy with the drug Afinitor®, the exclusion of the infectious process, if necessary, the use of glucocorticosteroids to reduce the severity of symptoms to 1 degree. Resumption of therapy with the drug Afinitor® in a reduced dose. Discontinuation of therapy with the drug Afinitor®, if the reduction in the severity of symptoms to 1 degree did not occur within 3 weeks.
	Degree 3 Symptoms that affect the daily life; use of oxygen therapy	Discontinuation of therapy with the drug Afinitor® until the severity of symptoms is reduced to 1 degree, excluding the infectious process, if necessary, applying glucocorticosteroids. Resumption of therapy with the drug Afinitor® in a reduced dose. With the re-development of symptoms to grade 3, discontinuation of therapy with the drug Afinitor®.
	Degree 4 Life-threatening condition; use of respiratory support methods	The termination of therapy with the drug Afinitor®, the exclusion of the infectious process, if necessary the use of glucocorticosteroids.
Stomatitis	Degree 1 Symptoms of mild severity; a special diet is not required	Dose adjustments are not required Rinse your mouth non-alcoholic or water-salt solutions (0.9%) several times a day.
	Degree 2 Symptoms of secondary severity with the ability to ingest and swallow; required special diet	Discontinuation of therapy with the drug Afinitor® until the severity of symptoms is reduced to 1 degree. Renewal of therapy with the drug Atinitor® in the previous dose. With the repeated development of symptoms of stomatitis to grade 2 - discontinuation of therapy with the drug Afinitor ® to reduce the severity of symptoms to 1 degree. Renewal of therapy with the drug Atinitor® in the previous dose. Treatment with analgesics for external use (benzocaine, butyl-aminobenzoate, tetracaine hydrochloride, menthol or phenol) with or without glucocorticosteroids for external use³.
	Degree 3 Pronounced symptoms; ability to eat and liquids inside is limited	Discontinuation of therapy with the drug Afinitor® until the severity of symptoms is reduced to 1 degree. Resumption of therapy with the drug Afinitor® in a reduced dose. Treatment with analgesics for external use (benzocaine, butyl-aminobenzoate, tetracaine hydrochloride, menthol or phenol) with or without glucocorticosteroids for external use³.
	Degree 4 Life-threatening condition	Discontinuation of therapy with the drug Afinitor®, treatment of stomatitis by appropriate methods.
Other non-hematological toxicity (excluding metabolic disorders)	Degree 1	Correction of the dose is not required with tolerability of symptoms. Treatment by appropriate methods and monitoring of the condition.
	Degree 2	Correction of the dose is not required with tolerability of symptoms. Treatment by appropriate methods and monitoring of the condition. If the symptoms are intolerant, discontinue therapy with the drug Afinitor® until the severity of symptoms is reduced to 1 degree. Renewal of therapy with the drug Atinitor® in the previous dose.
	Degree 3	Discontinuation of therapy with the drug Afinitor® until the severity of symptoms is reduced to 1 degree. Treatment by appropriate methods and monitoring of the condition. Resumption of therapy with the drug Afinitor in a reduced dose. With the re-development of symptoms to grade 3, discontinuation of therapy with the drug Afinitor®
	Degree 4	Discontinuation of drug therapy, treatment with appropriate methods.
Metabolic disorders (eg, hyperglycemia, dyslipidemia)	Degree 1	Correction of the dose is not required with tolerability of symptoms. Treatment by appropriate methods and monitoring of the condition.
	Degree 2	A dose change is not required if symptoms are tolerated. Treatment by appropriate methods and monitoring of the condition.
	Degree 3	Temporary discontinuation of therapy with the drug Afinitor®. Resumption of therapy with the drug Afinitor® in a reduced dose. Treatment by appropriate methods and monitoring of the condition.
	Degree 4	Discontinuation of therapy with the drug Afinitor®, treatment with appropriate methods.

1 Degrees of severity: 1 = minimal symptoms; 2 = moderate symptoms; 3 = severe symptoms; 4 = life-threatening symptoms.
2If a dose reduction is required, a dose of approximately 50% less than the previous dose is recommended.
3 Avoid the use of drugs containing alcohol, hydrogen peroxide, iodine and thyme derivatives in the treatment of stomatitis (can provoke an increase in ulceration in the oral cavity).
Application simultaneously with moderate inhibitors of the isoenzyme CYP3A4 or inhibitors of P-GP
When used concomitantly with moderate inhibitors of the isoenzyme CYP3A4 or inhibitors of P-GP, the dose of the drug Afinitor® should be reduced by 50%. Further dose reduction may be required in the development of severe and / or intolerable adverse events.
If you stop taking a moderate inhibitor of the isoenzyme SURZA4 / R-GP, you should ensure a period of elimination from the body for at least 2-3 days (mean elimination time for the most commonly used moderate inhibitors of the isoenzyme SURZA4 / R-GP) Athenitor®. The dose of the drug Afinitor® should be returned to the initial one and after 2 weeks the concentration of everolimus in the blood plasma should be measured.
Application simultaneously with the powerful inductors of the isoenzyme CYP3A4
When using the preparation of the Athenitor® simultaneously with the powerful inducers of the CYP3A4 isoenzyme, it may be necessary to increase the daily dose by a factor of 5 mg or less based on the pharmacokinetic data. It is assumed that with this change in the dose of the drug Afinitor®, the AUC value will correspond to the AUC observed without the isoenzyme inducers, however, there are no clinical data with a similar dose change in patients receiving potent inducers of the CYP3A4 isoenzyme.If the CYP3A4 isoenzyme is discontinued, it should be taken out of the body for at least 3-5 days (an adequate period to significantly reduce the induction of this isoenzyme), before reducing the dose of the drug Atinitor® to the initial dose.
Patients aged ≥ 65 years old: dosage adjustment is not required.
Patients with impaired renal function: dosage adjustment is not required.
Patients with impaired hepatic function
In patients with impaired hepatic function possible use of the drug Afinitor® in tablet dosage form 2.5 mg per day.
In patients with mild liver function disorders (class A according to Child-Pugh classification), the recommended dose is 7.5 mg per day.
In patients with impaired liver function of an average degree (class B according to the Child-Pugh classification), the recommended dose is 5 mg per day; if the drug is poorly tolerated, a dose reduction of up to 2.5 mg per day is possible.
-In patients with violations of liver function of severe degree (class C according to the Child-Pugh classification) the drug is not recommended. In cases where the possible benefit exceeds the risk, it is possible to take everolimus at a maximum dose of 2.5 mg per day.
In the case of a change in the severity of the liver function disorder (Child-Pugh classification), it is necessary to adjust the dose of the drug Afinitor®.
In patients with mild liver function disorder (class A Child-Pugh classification), the recommended dose is 7.5 mg per day.
In patients with impaired liver function of moderate severity (class B according to the Child-Pugh classification), the recommended dose is 5 mg per day; if the drug is poorly tolerated, a dose reduction of up to 2.5 mg per day is possible.
In patients with severe liver failure (class C according to the Child-Pugh classification), the drug is not recommended. In cases where the possible benefit exceeds the risk, it is possible to take everolimus at a maximum dose of 2.5 mg per day.
In the case of a change in the severity of the liver function disorder (Child-Pugh classification), it is necessary to adjust the dose of the drug Afinitor®.

Side effects:Spread and / or metastatic renal cell cancer or melastaticheskie neuroendocrine tumors of the gastrointestinal tract, lung and pancreas, hormone-dependent breast cancer common
When using the drug, the most frequent adverse events (frequency ≥ 10%) were (as the frequency of occurrence decreased): stomatitis, skin rash, fatigue, diarrhea, infections, nausea, decreased appetite, anemia, change in taste perception, pneumonitis, hyperglycemia, decrease body weight, itching, asthenia, peripheral edema, hypercholesterolemia, epistaxis, headache.
The most frequent AE of 3-4 degrees of severity (frequency ≥1 / 100 - <1/10) were: stomatitis, anemia, hyperglycemia, fatigue, infections, pneumonitis, diarrhea, asthenia, thrombocytopenia, neutropenia, dyspnea, lymphopenia, proteinuria, bleeding , hypophosphatemia, skin rash, arterial hypertension, increased activity of aspartate aminotransferase (ACT), increased activity of alanine aminotransferase (ALT), pneumonia.
Below are the AEs that occurred with the use of the drug Afinitor® (at a dose of 10 mg per day), indicating the frequency of their occurrence: very often (≥1 / 10), often (≥1 / 100 and <1/10), infrequently (≥ 1 / 1000 and <1/100), rarely (≥1 / 10000 and <1/1000), very rarely (<1/10000), including individual messages.
AEs are grouped according to the classification of organs and systems of organs of MedDRA, within each group are listed in order of decreasing frequency of occurrence.
Infectious and parasitic diseases: very often - infections (including pneumonia, shingles, sepsis, single cases of opportunistic infections (aspergillosis, candidiasis, viral hepatitis B)).
Violations from the blood and lymphatic system: very often - anemia; often - thrombocytopenia, neutropenia, leukopenia, lymphopenia; infrequently - pancytopenia; rarely - a true erythrocyte aplasia of the bone marrow.
Immune system disorders: infrequently, hypersensitivity reactions.
Disorders from the metabolism and nutrition: very often - a decrease in appetite, hyperglycemia, hypercholesterolemia; often - hypertriglyceridemia, hypophosphatemia, diabetes mellitus, hyperlipidemia, hypokalemia, dehydration, hypocalcemia.
Disorders of the psyche: often - insomnia.
Impaired nervous system: very often - a change in the perception of taste, a headache; infrequently - loss of taste sensitivity.
Disorders from the side of the organ of vision: often - swelling of the eyelids; infrequently - conjunctivitis.
Heart Disease: infrequently chronic heart failure.
Vascular disorders: often - bleeding, increased blood pressure (BP), bleeding; infrequently - "hot flashes", deep vein thrombosis.
Disturbances from the respiratory system, chest and mediastinal organs: very often - pneumonitis (including alveolitis, interstitial lung disease, alveolar pulmonary hemorrhages, pulmonary infiltration, pulmonary toxicity), nosebleeds; often - cough, shortness of breath; infrequently - pulmonary embolism, hemoptysis; rarely acute respiratory distress syndrome.
Disorders from the digestive system: very often - stomatitis (including aphthous stomatitis and ulceration of the mucous membrane of the tongue and oral cavity, glossitis, glossalgia), diarrhea, nausea; often - vomiting, dryness of the oral mucosa, pain in the oral cavity, abdominal pain, indigestion, dysphagia.
Disturbances from the skin and subcutaneous tissues: very often - skin rash, itching; often - dry skin, damage to the nail plates, alopecia, acne, increased fragility of nail plates, syndrome of palmar-plantar erythrodysesthesia, skin peeling, erythema, damage to the skin; rarely - angioedema.
Disturbances from the musculoskeletal and connective tissue:often - arthralgia.
Disorders from the kidneys and urinary tract: often proteinuria, renal insufficiency; infrequent - frequent urination during the day, acute renal failure.
Violations of the genitals and breast: often - an irregular menstrual cycle; infrequently, amenorrhea.
General disorders and disorders at the site of administration: very often - increased fatigue, asthenia, peripheral edema; often - inflammation of the mucous membranes, increased body temperature; infrequently - non-cardiogenic chest pain; rarely - slow healing of wounds.
Laboratory and instrumental indicators: very often - a decrease in body weight.
Deviations of laboratory and instrumental indicators, marked with a frequency of ≥10% (gradation "very often", AE are listed as the frequency of occurrence decreases): decrease in hemoglobin concentration, lymphopenia, leukopenia, thrombocytopenia, neutropenia, increased fasting blood glucose, cholesterol, triglycerides, increased ACT activity, hypophosphatemia, increased ALT activity, increased creatinine concentration, hypokalemia.
The majority of laboratory abnormalities were of mild to moderate severity.Severe (3-4 degree) abnormalities included: lymphopenia, decreased hemoglobin concentration, neutropenia, thrombocytopenia, leukopenia, increased blood glucose, hypophosphatemia, hypokalemia, increased activity of ACT, ALT, and increased serum creatinine, cholesterol, triglyceride concentrations
Side effects, revealed in clinical trials with the use of the drug in patients with tuberous sclerosis
When using the drug, the most frequent adverse events (frequency ≥ 1/10), AEs are listed as the incidence decreases) were: stomatitis, amenorrhea, upper respiratory tract infections, hypercholesterolemia, nasopharyngitis, irregular menstrual cycle, acne, sinusitis, otitis media and pneumonia. The most frequent adverse events (AE) of 3-4 degrees of severity (frequency ≥ 1/100 - <1/10) were: stomatitis, amenorrhea, pneumonia, neutropenia, fever, viral gastroenteritis, inflammation of subcutaneous fat.
Below are the AEs that occurred with the use of the drug Afinitor (10 mg per day), indicating the frequency of their occurrence: very often (≥1/10), often (≥1 / 100 - <1/10), infrequently (≥1 / 1000 - <1/100), rarely (≥1 / 10000 - <1/1000), very rarely (<1/10000), including individual messages.

AEs are grouped according to the classification of organs and systems of organs of McdDRA, within each group are listed in order of decreasing frequency of occurrence.

Infectious and parasitic diseases: very often - infections of the upper respiratory tract, nasopharyngitis, sinusitis, otitis media, pneumonia; often - urinary tract infections, pharyngitis, inflammation of the subcutaneous tissue, streptococcal pharyngitis, gastroenteritis of viral ethnology, gingivitis, shingles; infrequently - a bronchitis of a virus etiology.
Violations from the blood and lymphatic system: often neutropenia, anemia, leukopenia, lymphopenia, thrombocytopenia.

Immune system disorders: often - hypersensitivity reactions.

Disorders from the metabolism and nutrition: very often hypercholesterolemia; often - a decrease in appetite, hypertriglyceridemia, hypophosphatemia, hyperglycemia.

Disorders of the psyche: often - irritability, aggression; infrequently - insomnia.

Impaired nervous system: often - a headache, a change in the perception of taste.

Vascular disorders: often - increased blood pressure pressure, lymphedema.

Disturbances from the respiratory system, chest and mediastinal organs: often - coughing, nosebleeds; infrequently - pneumonitis.

Disorders from the digestive system: very often - stomatitis (including aphthous stomatitis, ulceration of the oral mucosa, lips, glossitis, pain in the gums); often - diarrhea, nausea, vomiting, abdominal pain, pain in the oral cavity, flatulence, constipation, gastritis.

Disturbances from the skin and subcutaneous tissues: very often - acne; often a rash (including rash, erythema rash, erythema, maculopulular rash, macular rash, generalized rash), acneiform dermatitis, dry skin; infrequently - angioedema.

Disorders from the kidneys and urinary tract: often proteinuria.

Violations of the genitals and breast: very often - amenorrhea, irregular menstrual cycle; often - vaginal bleeding, uterine bleeding, ovarian cyst, opsonenorea.

General disorders and disorders at the site of administration: often - increased fatigue, increased body temperature.

Laboratory and instrumental data: often - increased lactate dehydrogenase (LDH) activity,increase in the concentration of lutesinizing hormone (LH) in the blood plasma; infrequently - an increase in the concentration of follicle-stimulating hormone (FSH) in the blood plasma.

Deviations of laboratory and instrumental indicators, marked with a frequency ≥ 1/10 (as the frequency of occurrence decreases)

Hematologic: increased partial thromboplastin time, reduced serum hemoglobin concentration, decreased absolute neutrophil count, leukopenia, lymphocyte and thrombocytopenia.

biochemical: hypercholesterolemia, hypertriglyceridemia, increased activity of ACT, ALT, hypophosphatemia, increased activity of alkaline phosphatase (SHF), increased plasma glucose concentration in the fasting blood, hypokalemia.

Most of the above adverse events were mild (1 st) or medium (2 nd) severity.

Deviations of a serious degree (grade 3-4) included:

hematological: often - decrease in the absolute number of neutrophils, decrease in hemoglobin concentration, increase in partial thromboplastin time, lymphopenia; infrequently, leukopenia; - biochemical, often - hypophosphatemia, increased activity of alkaline phosphatase, ginertriglyceridemia,increased ACT activity; infrequently, hypercholesterolemia, increased ALT activity, decreased potassium in blood plasma, increased fasting blood glucose.

Description of individual adverse events according to clinical studies and the use of everolimus in clinical practice in the post-marketing period
There have been cases of exacerbation of viral hepatitis B, some with a legal outcome. Exacerbation of infections is an expected phenomenon during periods of immunosuppression.
There were cases of renal failure (including fatal outcome) and proteinuria. It is recommended to monitor kidney function.
There were cases of amenorrhea (including secondary amenorrhea).
There have been cases of pneumocystis pneumonia, some with a fatal outcome.
There have been cases of angioedema development both with simultaneous use with ACE inhibitors, and with isolated application of everolimus. The adverse events that developed with the use of everolimus in patients aged 65 years and older often required discontinuation of therapy. Most often such phenomena included: pneumonitis (incl.interstitial lung disease), stomatitis, fatigue and dyspnea.
If you notice a worsening of the clinical course of any of the side effects listed in the manual, or you notice any other side effects not listed in the instructions, tell your doctor.

Overdose:No cases of drug overdose have been reported. In the case of an overdose of the drug, the Athinitor® should be monitored by the patient, and appropriate symptomatic therapy should be applied. With a single dose of the drug inside at doses up to 70 mg, its tolerability was satisfactory.

Interaction:

Everolimus is a substrate of isoenzyme CYP3A4, as well as a substrate and moderately active inhibitor of P-glycoprotein (P-GP pump), providing efflux from cells of many drug compounds. Therefore, the absorption and subsequent excretion of everolimus can be influenced by substances that interact fromisoenzyme CYP3A4 and / or P-GP.

In vitro everolimus exhibits the properties of a competitive inhibitor of isoenzyme CYP3A4 and a mixed isoenzyme inhibitor CYP2D6.

Drugs (drugs) that can change the concentration of everolimus in the blood:

Drugs

ChangeAUC and FROM_m_Oheverolimus

Recommendations for

simultaneous

application

Powerful inhibitors of SURZA4 / R-GP

Ketoconazole

AUC

increased 15.3 times

FROM_m_Oh

increased 4.1-fold

Simultaneous use with the drug Afnnntor® is not recommended.

Itraconazole

Posaconazole

Voriconazole

Simultaneous

application is not

studied,

expected

significant

rise

concentrations

everolimus.

Telithromycin

Clarithromitsi

Mr.

Nefazodone

Ritonavir

Atazanavir

Saquinavir

Darunavir

Indinavir

Nelfi Navir

SURZA4 / R-GP inhibitors with moderate activity

Erythromycin

AUC

increased by 4.4 times C_m_Oh

increased 2.0 times

Be careful with the simultaneous use, the dose of Afnnntor® should be reduced.

Imatnib

AUC

increased 3.7 times

FROM_m_Oh

increased 2.2 times

Verapamil

AUC

increased 3.5 times FROM_max

increased 2.3 times

Cyclosporin

AUC

increased in

time

FROM_m_Oh

increased in

time

Fluconazole

Diltiazem

Simultaneous

application is not

studied,

expected

rise

concentrations

everolimus.

Dronedaron

Simultaneous

application is not

studied,

expected

rise

concentrations

everolimus.

Amprenavir

Fosamprenavir

Simultaneous

application is not

studied,

expected

rise

concentrations

everolimus.

G raipfruit,

grapefruit

juice, fruit

carambola

(tropical

stars),

bitter

orange and

others

products,

affecting

activity

cytochrome P450

and P-GP.

Simultaneous

application is not

studied,

expected

rise

concentrations

everolimus.

Simultaneous use with the drug Afinitor® should be avoided.

Powerful inductors CYP3A4

Rifamycin

AUC

decreased by 63%

FROM_m_Oh

decreased in 58%

Simultaneous use with the drug Afinitor® should be avoided. If concomitant use is necessary, the dose of Afinitor® should be increased.

G Lucocorticos

theroids

(eg,

dexamethasone,

prednisone,

prednisolone)

Simultaneous

application is not

studied,

expected

decrease

concentrations

everolimus.

Carbamazepine

Phenobarbital

Fsnitoin

Simultaneous

application is not

studied,

expected

decrease

concentrations

everolimus.

Efavirenz

Nevirapine

Simultaneous

application is not

studied,

expected

decrease

concentrations

everolimus.

St. John's Wort

perforated

Simultaneous application has not been studied, a significant decrease in the concentration of everolimus is expected.

Simultaneous use with the drug Afinitor® is not recommended.

Effect of everolimus on plasma concentration in plasma used as concomitant therapy

In healthy volunteers, the simultaneous use of everolimus with atorvastatin (substrate of the isoenzyme CYP3A4) or pravastatin (not a substrate of the isoenzyme CYP3A4) has not been observed clinically significant pharmacokinetic interaction. In the population pharmacokinetic analysis, the effect of simvastatin (the substrate of the isoenzyme CYP3A4) on the clearance of everolimus was also not revealed.

In vitro everolimus competitively inhibited the metabolism of the substrate of the isoenzyme CYP3A4-cyclosporin and was a mixed inhibitor of the substrate of the CYP2D6 isoenzyme dextromethorphan. Average stationary C_m_Oh everolimus when taking the drug inside at a dose of 10 mg per day or 70 mg per week is more than 12-36 times lower than the K_i everolimus inhibitory effect in vitro on the isozymes CYP3A4 and CYP2D6. Therefore, the effect of everolimus in vivo on the metabolism of substrates of isoenzymes CYP3A4 and CYP2D6 is unlikely.

The combined use of everolimus and midazolam leads to an increase in the stanza of midazolam by 25% and an increase in AUC_(o-inf)midazolam by 30%, while the metabolic ratio of AUC (1-hydroxymidazolam / midazolam) and half-life of midazolam did not change. This suggests that the increased exposure of midazolam is a consequence of the effects of everolimus in the gastrointestinal tract, when both drugs are taken at the same time. therefore everolimus can affect the bioavailability of concomitantly ingested drugs, which are substrates of the isoenzyme CYP3A4. It is unlikely that everolimus changes the exposure of other drugs that are substrates of CYP3A4, administered not inward, but in other ways, for example, intravenously, subcutaneously and transdermally.

The simultaneous use of everolimus and exemestane results in an increase in C_m_Oh and C₂_h the latter by 45% and 71%, respectively. However, the corresponding levels of estradiol in the equilibrium state (4 weeks) did not differ in the two treatment groups. In postmenopausal women with hormone-dependent common breast cancer with positive hormonal receptors who received the appropriate combination, there was no increase in the incidence of side effects.The effect of this increase in the concentration of exmestane on its effectiveness and safety is unlikely.

The combined use of everolimus and octreotide prolonged action leads to an increase C_m_i_n octreotide (with a geometric mean of 1.47), with little effect on the clinical effect of everolimus in patients with advanced neuroendocrine tumors.

Vaccination

Immunosuppressants may influence the response during vaccination; against the background of treatment with the drug Afinitor® vaccination may be less effective. Use of live vaccines and close contact with persons vaccinated with live vaccines should be avoided.

Special instructions:Treatment with drug Afinitor® should be carried out only under the supervision of a doctor who has experience working with antitumor drugs.
During therapy with the drug Afinitor® and a minimum of 8 weeks after the end should be used reliable methods of contraception.
Before the beginning of treatment with the drug Afinitor® and periodically during therapy, kidney function should be monitored, including measurement of blood urea nitrogen concentration, urinary protein concentration or serum creatinine concentration, and a clinical blood test.
Before the beginning of treatment with the drug Afinitor® and periodically during therapy should monitor the concentration of glucose in the blood serum on an empty stomach. It is necessary to ensure adequate control of blood glucose concentration before the beginning of treatment with the drug Afinitor®.
Before the beginning of treatment with the drug Afinitor® and periodically during therapy should monitor the concentration of cholesterol and triglycerides.
Before the beginning of treatment with the drug Afinitor® and periodically during therapy should monitor the content of blood cells.
Noninfectious pneumonitis is a class-specific side effect of rapamycin derivatives. With the use of the drug Afinantor® There have also been cases of development of noninfectious pneumonitis (including interstitial lung disease). In some cases, severe forms of the disease (rarely fatal) were observed. The diagnosis of noninfectious pneumonitis should be assumed in the development of such nonspecific manifestations from the respiratory organs as hypoxia, effusion to the pleural cavity, coughing or shortness of breath, and also by excluding, through appropriate diagnostic tests, the infectious, tumor and other causes of such manifestations.When conducting differential diagnosis of noninfectious pneumonitis, opportunistic infections, for example, pneumocystis pneumonia, should be excluded.
The patient should be informed to the treating physician of any new or increased respiratory symptoms. Patients who have only x-ray signs of nonsinfective pneumonitis (in the absence or in the presence of minimal clinically significant symptoms) may continue treatment with the drug Afinitor® without dose adjustment. If the symptoms of pneumonitis are moderately expressed, consideration should be given to temporarily suspending therapy until symptoms disappear. For relief of symptoms, the use of glucocorticosteroids is possible. Treatment with the drug can be resumed at a dose 50% below the baseline.
With the development of severe symptoms (grade 3 or 4) of nonsinfective pneumonitis, therapy with the drug Afinitor® should be discontinued until the severity of symptoms is reduced to 1 degree. For relief of symptoms, the use of glucocorticosteroids is possible. Depending on the clinical conditions after the treatment of pneumonitis, therapy with the drug can be resumed at a dose 50% lower than the initial one (see Fig.Method of administration and dose). With the re-development of symptoms up to grade 3 therapy with the drug Afinitor® should be discontinued. Also received a report on the development of pneumonitis with the drug Afinitor® in a reduced dose.
In patients receiving glucocorticosteroid preparations for the treatment of noninfectious pneumonitis, the possibility of preventing the development of pneumocystis pneumonia should be considered.
Preparation of the Athenter® has immunosuppressive properties and can promote the development of bacterial, fungal, viral or protozoal infections, especially those caused by conditionally pathogenic microorganisms. In patients who took the drug Athenter®, cases of local and systemic infections, including pneumonia, other bacterial infections, fungal infections such as aspergillosis or candidiasis, pneumocystis pneumonia and viral infections, including exacerbation of viral hepatitis B have been described. Some of these infections have been severe (with the development of sepsis, respiratory or liver failure) and sometimes lead to death.Patients should be informed of the increased risk of infection with the drug Afinitor®, be attentive to the symptoms and signs of infections and when they appear, contact the doctor in a timely manner. Patients with infections should be treated appropriately before using Afinitor®.
In case of development of an invasive systemic fungal infection, therapy with the drug Atinitor® should be canceled and appropriate antifungal therapy should be carried out.
Patients treated with the drug Afinitor® experienced ulceration of the oral mucosa, stomatitis and inflammation of the oral mucosa. In such cases, local therapy is recommended, however, oral rinse products containing alcohol, hydrogen peroxide, iodine and thyme derivatives, since their use can worsen the condition. Antifungal agents should be used only in case of confirmation of fungal infection.
Patients receiving treatment with everolimus, described cases of pneumocystis pneumonia, some with a fatal outcome.The development of pneumocystis pneumonia can be associated with the simultaneous use of glucocorticosteroids or other immunosuppressive drugs. In the case of simultaneous treatment with glucocorticosteroids or other drugs that depress the immune system, consideration should be given to the possibility of preventing the development of pneumocystis pneumonia.
Hypersensitivity reactions in the use of everolimus included, but were not limited to, anaphylactic shock, dyspnea, redness of the skin, chest pain, or angioedema (eg, swelling of the airways or tongue with / without respiratory function).
Patients receiving concurrent treatment with ACE inhibitors may have an increased risk of angioedema (eg, swelling of the airways or tongue with / without respiratory function).

Effect on the ability to drive transp. cf. and fur:Studies of the effect of the drug Afinitor® on the ability to drive vehicles and mechanisms were not conducted. Given the possibility of developing some adverse reactions against the background of taking the drug Afinitor® (fatigue, dizziness, drowsiness),patients should be careful when driving vehicles and engaging in other potentially hazardous activities that require increased concentration.

Form release / dosage:

Tablets of 5 mg and 10 mg.

Packaging:

10 tablets in a blister pack. For 3, 6 or 9 blisters together with instructions for use in a cardboard bundle.

Storage conditions:At a temperature of no higher than 30 ° C, in a dry, protected from light place.
Keep out of the reach of children.

Shelf life:

3 years.

Do not use the drug after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LSR-002260/10

Date of registration:18.03.2010 / 22.07.2014

The owner of the registration certificate:Novartis Pharma AGNovartis Pharma AG Switzerland

Manufacturer: & nbsp

NOVARTIS PHARMA STEIN, AG Switzerland

Representation: & nbspNOVARTIS PHARMA LLCNOVARTIS PHARMA LLC

Information update date: & nbsp2016-01-23

Illustrated instructions

Instructions

Athenitor® (Afinitor)