Athenitor® (Afinitor)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceEverolimusEverolimus
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  • Athenitor®
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    Novartis Pharma AG     Switzerland
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    pills inwards 
    Novartis Pharma AG     Switzerland
  • Athenitor®
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    Novartis Pharma AG     Switzerland
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  • Sertikan
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    Novartis Pharma AG     Switzerland
    • Dosage form: & nbsppills
    Composition:

    1 the tablet contains: active substance - everolimus (stabilized through 0,2% butylhydroxyntoluene 0.005 mg) 2.5 mg;

    auxiliary substances: lactose 71.875 mg,

    crospovidone 25,000 mg,

    hypromellose 22,500 mg,

    lactose monohydrate 2,450 mg,

    magnesium stearate 0.625 mg,

    butylhydroxytoluene 0.055 mg.

    Description:

    Tablets 2.5 mg: flat, oblong pills with a bevel, from white to white with a yellowish hue of color, embossed “NYR" on one side and “LCL” another.

    Pharmacotherapeutic group:An antitumour agent, a 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 tumor suppressor genes: Tuberous Sclerosis 1 and 2 genes (TSC1, TSC2). In tuberous sclerosis (TC), a genetically conditioned disease, inactivating mutations in one or both of the 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 antiangiogenic therapy by 67%, the survival rate of patients without disease progression 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 (assessment of the impact of the symptoms of the disease on various areas of the patient's life).

    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 that is activated in breast cancer cells, primary-resistant or have lost sensitivity to endocrine therapies with aromatase inhibitors or antiestrogens 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.

    Combination therapy of an aromatase inhibitor everolimus and allows to increase progression-free survival and 2.6 times, respectively, by 64% to reduce the likelihood of disease progression and death.

    The use of everolimus in patients with kidney / kidney angiomyolipoma associated with tuberous sclerosis leads to a statistically significant decrease in neoplasm volume and a slowing down of the progression of angiomyolipoma.

    In patients with subependymal giant cell astrocytomas (CEGA) associated with TC, a significant decrease in tumor volume was noted after 6 months of treatment with everolimus, with 75% of patients having a reduction in tumor volume of at least 30%, and 32% of patients not less than than by 50%. In this case, new foci, increased hydrocephalus, signs of increased intracranial pressure and the need for surgical treatment of SEGA did not arise.

    Pharmacokinetics:

    Suction

    The maximum concentration (Cmax) 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. FROMmax 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 or more, an increase in Cmax occurs less than proportionally to the dose, but the area under the concentration-time curve (AUC) increases in proportion to the dose from 5 mg to 70 mg of the drug.

    When taking everolimus in a dose of 10 mg in the form of tablets with food with a high content of fat AUC and Cmax of the drug decreased by 22% and 54%, respectively.

    Simultaneous intake of food with a low fat content reduced AUC and Cmax 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 a decrease in Cmax 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 the everolimus concentration in the 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%. The amount of everolimus in the blood plasma is about 20% of its quantity in whole blood at the substance concentrations recorded in the blood of patients with cancer taking 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. It is generally believed 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 or weekly dose of everolimus, the AUC0-τ were proportional to the dose of the drug when used in doses of 5 to 10 mg per day. The equilibrium state was achieved within two weeks with the daily administration of everolimus. FROMmax everolimus 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 (Tmax) was 1-2 hours. With the daily administration of everolimus upon reaching the equilibrium state, there was a significant correlation between AUC0-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, if the liver function is mild (Class A according to the Child-Pugh classification), medium severity (class B according to 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.

    - In patients with SEGA, the individual equilibrium minimum therapeutic concentration (Cmin) everolimus was directly proportional to the daily dose and was in the range of 1.35 - 14.4 mg / m2.

    - In patients with SEGA, the geometric mean of the minimum therapeutic concentration of everolimus normalized to the dose in mg / m2 in patients younger than 10 years and 10 to 18 years is statistically significantly lower than in adult patients, which may indicate an increased clearance of everolimus in young patients.

    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 an average minimum concentration (Cmin) everolimus in the blood in an 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 values ​​of Cmin Everolimus, determined in the blood with a daily intake of the drug at a dose of 10 mg.

    It was shown that in patients with SEGA, an increase in Cmin in 2 times leads to a decrease in the tumor size by 13%, while a decrease in the tumor size by 5% is statistically significant.

    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.

    Subependymal giant cell astrocytomas associated with tuberous sclerosis in patients over the age of 3 years with the impossibility of performing surgical resection of the tumor.

    Angiomyolipoma of the kidney, associated with tuberous sclerosis, does not require immediate surgical intervention.

    Contraindications:

    - Hypersensitivity to everolimus, other derivatives of rapamycin or any of the auxiliary components of the drug.

    -Explained violations of liver function in patients over 18 years of age with sub-ependymal giant cell astrocytomas (class C according to the Child-Pugh classification) and liver function disorders (class A, B, C according to Child-Pugh classification) in patients from 3 to 18 years with subependymal giant-cell astrocytomas.

    -Pregnancy and the period of lactation.

    -Year up to 3 years (sub-ependymal giant-cell astrocytomas), to 18 years (according to other indications).

    It is not recommended simultaneous use with potent inhibitors of the isoenzyme CYP3A4 and / or P-GP. Avoid simultaneous application of everolimus with powerful inducers of the isoenzyme CYP3A4 or inducers of P-glycoprotein (P-GP pump).

    Carefully:
    Caution should be exercised while using everolimus with moderate inhibitors of CYP3A4 or inhibitors of P-GP.
    Everolimus is not recommended for severe hepatic insufficiency (Child-Pugh class C), except when the benefits of taking the drug exceed the possible risk (for all indications except for SEGA).
    Since rapamycin derivatives, including the drug Afinitor®, can slow the wound healing process, care should be taken when prescribing the drug to patients before surgery.
    Caution should be exercised when using the drug Afinitor® in patients with lactose intolerance, severe lactase deficiency or glucose-galactose malabsorption.
    Pregnancy and lactation:

    The drug Atinitor® is contraindicated for use during pregnancy and breastfeeding.

    During therapy with the drug Atinitor® and at least 2 months after the end of therapy, reliable methods of contraception should be used.

    Fertility

    Data on the effect of the drug Afinitor® on the fertility of men and women do not.

    However, based on the results of preclinical studies, it can be concluded that therapy with the drug Afinitor® can adversely 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. If patients for health reasons are unable to swallow whole tablet, the tablet formulation Afinitor® recommended completely dissolve in a glass of water (about 30 mL), gently stirring immediately before administration. After taking the glass it is recommended to rinse with the same amount of water and get the resulting solution to drink to ensure the reception of the full dose of the drug. Treatment with the drug is carried out as long as the clinical effect remains and there are no signs of intolerable toxicity.
    - Distribution and / or metastatic renal cell carcinoma after failure of 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.
    - Sub-ependymal giant cell astrocytomas associated with tuberous sclerosis in patients over 3 years of age when surgical resection of the tumor is not possible.
    The initial dose of the drug is determined based on the surface area of ​​the body, calculated by the Dubois formula. The recommended initial dose of the drug Afinitor® for the treatment of patients with SEGA is 4.5 mg / m2 , rounded to the nearest dosage of the drug Afinitor®. The tablets of the preparation Afinitor® of various dosages can be combined to obtain the required dose. Patients receiving everolimus therapy for SEGA should monitor the concentration of everolimus in the blood. The concentration of everolimus in the blood should be assessed approximately 2 weeks after the start of treatment. Cmin the drug in the blood should be in the range of 5-15 ng / ml.After initiation of therapy with the drug Afinitor®, the volume of the CEGA tumor should be evaluated every 3 months. With individual dose selection, the tumor response to treatment, the concentration of everolimus in the blood, and the individual tolerance of the drug should be considered. Once the dose has been selected, the concentration of everolimus in the blood plasma should be determined every 3 to 6 months in patients whose body surface area changes or every 6-12 months in patients whose body surface area remains unchanged throughout the treatment period.
    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, it is recommended to reduce the dose by approximately 50% from the previous dose. In patients receiving 2.5 mg of the drug Afinitor® per day, further reduction of the dose, if necessary, is possible with taking the drug every other day.
    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 severity

    Recommendations for dose modification and correction of adverse events2

    Noninfectious pneumonitis

    Degree 1

    Absence of symptoms, except for radiographic signs

    A dose change 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, the use of 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 change is not required

    Rinse mouth with non-alcoholic or water-salt solutions (0.9%) several times a day.

    Degree 2

    Symptoms of moderate severity with preservation of ability to ingest and swallow; requires a 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

    A dose change is not required if symptoms are tolerated. 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. 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

    Renewal of the drug from a lower dose.

    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 therapy with the drug Afinitor®, treatment with appropriate methods.

    Metabolic disorders (eg, hyperglycemia, dyslipidemia)

    Degree 1

    Discontinuation of the drug and treatment with appropriate methods.

    A dose change is not required if symptoms are tolerated. 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.

    Degree 4

    Treatment by appropriate methods and monitoring of the condition.

    Discontinuation of therapy with the drug Afinitor®, treatment with appropriate methods.

    Application simultaneously with moderate inhibitors of the isoenzyme CYP3A4 or inhibitors of P-GP

    When applied simultaneously with moderate CYP3A4 isoenzyme inhibitors or P-HP inhibitors, the dose of the drug Afinitor® should be reduced by 50%. In patients receiving 2.5 mg of the drug Afinitor® per day, further reduction of the dose, if necessary, is possible with taking the drug every other day. Further dose reduction may be required in the development of severe and / or intolerable adverse events.
    - 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, kidney angiomyolipoma, not requiring immediate surgical intervention, in patients with tuberous sclerosis.
    If you stop taking a moderate inhibitor of the isoenzyme SURZA4 / R-GP, you should ensure a period of excretion from the body for at least 2-3 days of the wash-out period (the average elimination time for the most commonly used moderate inhibitors of the isoenzyme SURZA4 / R-GP) before increasing the dose of the drug Afinitor®.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.
    - Sub-ependymal giant cell astrocytomas associated with tuberous sclerosis in patients over 3 years of age when surgical resection of the tumor is not possible.
    The concentration of everolimus should be determined 2 weeks after the addition of moderate CYP3A4 isoenzyme inhibitors or P-GP inhibitors to therapy. If therapy with moderate CYP3A4 isoenzyme inhibitors or P-HP inhibitors is discontinued, the dose of the drug Afinitor® should be returned to the initial dose after 2-3 days of the washout period 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
    - A common and / or metastatic renal cell pack with ineffective antiangiogenic therapy; common and / or metastatic neuroendocrine tumors of the gastrointestinal tract, lung and pancreas, hormone-dependent common breast cancer, kidney angiomyolipoma, not requiring immediate surgical intervention, in patients with tuberous sclerosis.
    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 of the drug, without taking inductors of the isoenzyme CYP3A4, but clinical data with a similar dose change in patients receiving potent inducers of the CYP3A4 isoenzyme are absent. If the CYP3A4 isoenzyme is discontinued, 3-5 days of the washout period (an adequate period for a significant reduction in the induction of this isoenzyme) should be provided, until the dose of the drug Atinitor® is reduced to the initial dose.
    - Sub-ependymal giant cell astrocytomas associated with tuberous sclerosis in patients over 3 years of age when surgical resection of the tumor is not possible.
    When using the preparation of the Athenitor® simultaneously with the powerful inducers of the isoenzyme CYP3A4 (for example, antiepileptic drugs, such as carbamazepine, phenobarbital, phenytoin) it may be necessary to increase the dose of the drug to achieve a therapeutic concentration of 5-15 ng / ml; should increase the daily dose of the drug Afinitor® 2 times and assess the tolerance of the drug. After 2 weeks, the concentration of everolimus in the blood plasma should be measured. If necessary, adjust the dose of the drug Afinitor® to achieve a therapeutic concentration of 5-15 ng / ml. If you stop taking a powerful inducer of the isoenzyme CYP3A4, the dose of the drug Afinitor® should be returned to the initial one after 3-5 days of the washout period, and after 2 weeks the concentration of everolimus in the blood plasma should be measured.
    Patients under the age of 18 years

    In the treatment of SEGA in children and adolescents, the recommended doses are the same as for the treatment of adult patients with SEGA. Patients aged> 65 years: dose adjustment is not required.
    Patients with impaired renal function: dose adjustment is not required.
    Patients with impaired hepatic function
    - With widespread and / or metastatic renal cell carcinoma or metastatic neuroendocrine tumors of the gastrointestinal tract, lung and pancreas, with hormone-dependent widespread breast cancer, with angiomyolipoma of the kidney associated with the TC:

    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®.
    With sub-ependymal giant cell astrocytomas associated with tuberous sclerosis.
    Patients over 18 years of age
    Violation of the liver function of mild severity (class A according to the Child-Pugh classification): 75% of the dose calculated on the surface area of ​​the body (rounded to the nearest dosage).
    Violations of the function of the liver of moderate severity (class B according to the Child-Pugh classification): 25% of the dose calculated on the surface area of ​​the body (rounded to the nearest dosage).
    Violation of the liver function of a serious degree (class C according to the Child-Pugh classification): it is contraindicated.
    The concentration of everolimus in whole blood should be determined approximately 2 weeks after the start of treatment or after any change in liver function (Child-Pugh classification). In case of a change in the severity of the liver function disorder, it is necessary to adjust the dose of the drug Afinitor®.Titrate the dose to achieve a drug concentration in the range of 5 to 15 ng / ml.
    Therapeutic monitoring of the concentration of everolimus in plasma in patients with SEGA
    In patients with SEGA, the concentration of everolimus in blood plasma should be determined using validated bioanalytical methods of liquid chromatography / mass spectrometry. It is recommended that the same analytical method and laboratory be used whenever possible to monitor the concentration of everolimus in the blood plasma throughout the treatment period. Therapeutic monitoring of the everolimus concentration should be carried out within 2 weeks after the start of therapy, after any dose change or change in the dosage form of the drug, or the addition of SURCA4 / R-GP inhibitors or inducers to the therapy, or if there are signs of liver dysfunction.
    The dose should be titrated to the minimum therapeutic concentration (5-15 ng / ml), taking into account the tolerability of therapy by the patient. The dose can be increased to achieve a higher concentration of the drug in the blood (in the therapeutic range) and the optimal therapeutic effect, taking into account the patient's tolerability.

    Side effects:

    Common and / or metastatic renal cell carcinoma or metastatic neuroendocrine tumors of the gastrointestinal tract, lung and pancreas, hormone-dependent common breast cancer

    When using the drug, the most frequent adverse events (EH) (frequency ≥ 10%) were (as the frequency of occurrence decreased): stomatitis, skin rash, fatigue, diarrhea, infections, nausea, decreased appetite, anemia, change in taste perception, pneumonitis, peripheral edema, hyperglycemia, asthenia, pruritus, weight loss, hypercholesterolemia, epistaxis, cough, headache. The most frequent AH 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 aminotransferaseACT), increased activity of alanine aminotransferase (ALT), pneumonia and diabetes mellitus.

    Below are the AEs,The incidence 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 (≥ / 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 MedDRA, within each group are listed in order of decreasing frequency of occurrence.

    Infectious and parasitic diseases: very often - infections (including often pneumonia, urinary tract infections, infrequently bronchitis, shingles, sepsis, abscess, single cases of opportunistic infections (eg, aspergillosis, candidiasis, viral hepatitis B), rarely - myocarditis of viral etiology).

    Violations from the blood and lymphatic system: 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 - decreased 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 perception taste, headache; infrequently - loss 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 - increased blood pressure (BP), bleeding of various locations; 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 hemorrhage, pulmonary infiltration, pulmonary toxicity), epistaxis, cough; often 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, syndrome palmar-plantar erythrodysesthesia, erythema, acne, skin peeling, increased fragility of the nail plates, skin lesions, alopecia; 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 fatigue, asthenia, peripheral edema; often - increased body temperature, inflammation of the mucous membranes; infrequently - non-cardiogenic pain in the chest, slow healing of wounds.

    Laboratory and instrumental indicators: very often - weight loss.

    Deviations of laboratory and instrumental indicators, marked with a frequency ≥ 10% (gradation "very often", AE are listed as the frequency decreases inctractability):

    hematological - reduction of hemoglobin concentration, lymphopenia, leukopenia, thrombocytopenia, neutropenia;

    biochemical - increased fasting glucose, cholesterol, triglycerides, increased activity of ACT, hypophosphatemia, increased ALT activity, increased creatinine concentration, hypokalemia, decreased albumin concentration.

    The majority of laboratory abnormalities were of mild to moderate severity. Severe (3-4 degrees) deviations included:

    hematological - lymphopenia, decrease in hemoglobin concentration, neutropenia, thrombocytopenia, and leukopenia;

    biochemical - increase in glucose concentration (very often); hypophosphatemia, hypokalemia, increased activity of ACT, ALT, as well as an increase in the concentration of creatinine, cholesterol, triglycerides in serum, a decrease in the albumin concentration (often). Subependymal giant cell astrocytomas. associated with tuberous sclerosis, in patients older than 3 years with the impossibility of performing surgical resection of the tumor. angiomyolipoma of the kidney, associated with tuberous sclerosis, does not require immediate surgical intervention.

    In applying the drug most frequent AEs (frequency ≥ 10%; AEs are listed in descending order of frequency of occurrence) were stomatitis, nasopharyngitis, diarrhea, fever, upper respiratory tract infections, vomiting, cough, headache, amenorrhea, acne, rash, irregular menstrual cycle, pneumonia, sinusitis, urinary tract infections, fatigue, hypercholesterolemia, appetite deterioration. The most frequent AEs Grade 3-4 (frequency ≥ 1%) were: stomatitis, pneumonia, amenorrhea, neutropenia, fever, inflammation of the subcutaneous fat.

    Below are AEs occurred when applying the drug Afinitor® indicating the frequency of occurrence: very often (≥1 / 10), often (≥1 / 100 and <1/10) infrequently (≥ / 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 - nasopharyngitis, upper respiratory tract infections, pneumonia, sinusitis, urinary tract infections; often-pharyngitis, otitis media, inflammation of the subcutaneous tissue, streptococcal pharyngitis,gastroenteritis of viral etiology, gingivitis; infrequently - shingles, bronchitis of viral etiology.

    Violations from the blood and lymphatic system: often - anemia, neutropenia, leukopenia, thrombocytopenia, lymphopenia.

    Immune system disorders: often - hypersensitivity reactions.

    Disorders from the metabolism and nutrition: very often hypercholesterolemia, impaired appetite; often hypertriglyceridemia, hyperlipidemia, hypophosphatemia, hyperglycemia.

    Disorders of the psyche: often - insomnia, aggressiveness, irritability.

    Impaired nervous system: very often - headache; often - change the perception of taste.

    Vascular disorders: often - increased blood pressure, lymphedema.

    Disturbances from the respiratory system, chest and mediastinal organs: very often - cough; often - epistaxis; infrequently - pneumonitis.

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

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

    Disorders from the kidneys and urinary tract: often proteinuria.

    Violations of the genitals and breast glands: very often - amenorrhea *, irregular menstrual cycle * often - menorrhagia, vaginal bleeding, ovarian cyst; infremeness - opromenorea *.

    * - in patients aged 10 to 55 years who received therapy with the drug during clinical trials.

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

    Laboratory and instrumental data: often - increased lactate dehydrogenase (LDH) activity, increased concentration of luteinizing 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 ≥10% (as the frequency of occurrence decreases)

    Hematologic: increased partial thromboplastin time,a decrease in the absolute number of neutrophils, a decrease in the concentration of hemoglobin, leukopenia, thrombocytopenia, lymphopenia.

    Biochemical: hypercholesterolemia, hypertriglyceridemia, increased activity of ACT, increased activity of ALT, hypophosphatemia, increased activity of alkaline phosphatase (APF), increased fasting plasma glucose concentration.

    Most of the above AEs were mild (1 st) or medium (2 nd) severity. Severe (3-4 degrees) deviations included:

    - Hematologic: often - decrease in the absolute number of neutrophils, increase in partial thromboplastin time, decrease in hemoglobin concentration; infrequently - lymphopenia, leukopenia;

    - biochemical: often - hypophosphatemia, hypertriglyceridemia, increased activity of alkaline phosphatase; infrequently hypercholesterolemia, increased activity of ACT and ALT, increased fasting blood glucose concentration.

    Description of individual AEs 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, including cases with lethal outcome.Exacerbation of infections is an expected phenomenon during periods of immunosuppression.

    There have been cases of renal insufficiency (including fatal outcome) and proteinuria. It is recommended to monitor kidney function. There were cases of amenorrhea (including secondary amenorrhea).

    Cases were noted development of pneumocystis pneumonia (caused by Pneumocystis jirovecii), some with a fatal outcome.

    There have been cases of development angioneurotic edema as with simultaneous use with inhibitors of ACE, and with the isolated application of everolimus.

    Patients under the age of 18 years

    Have patients of this category, the main character, type, and frequency of AEs detected in clinical studies were similar. The results of clinical studies have not revealed a negative effect of everolimus on growth and development in pubertal period.

    Patients over the age of 65 years

    AEs 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 there is a deterioration in 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, inform the doctor about it.

    Overdose:No cases of drug overdose have been reported. In the case of an overdose of the drug Afinitor®, it is necessary to ensure observation of the patient, and also to prescribe appropriate symptomatic therapy. With a single dose of the drug inside at doses up to 70 mg, its tolerability was satisfactory.
    Interaction:

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

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

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

    Drugs

    Change in AUC and Cmax everolimus

    Recommendations for simultaneous use

    Powerful inhibitors of SURZA4 / R-GP

    Ketoconazole

    AUC increased 15.3 times

    Сmах increased in 4,1 times

    Simultaneous use with the drug Afinitor® is not recommended

    Itraconazole

    Posaconazole

    Voriconazole

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

    Telithromycin

    Clarithromycin

    Nefazodone

    Ritonavir

    Atazanavir

    Saquinavir

    Darunavir

    Indinavir

    Nelfinavir

    SURZA4 / R-GP inhibitors with moderate activity

    Erythromycin

    AUC increased 4.4 times

    Сmах increased in 2,0 times

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

    Imatinib

    AUC increased 3.7 times

    Сmах increased in 2,2 times

    Verapamil

    AUC increased 3.5 times

    Сmах increased by 2.3 times

    Cyclosporin

    AUC increased 2.7 times

    Сmах increased in 1,8 times

    Fluconazole

    Simultaneous application has not been studied, an increase in the concentration of everolimus is expected.

    Diltiazem

    Dronedaron

    Simultaneous application has not been studied, an increase in the concentration of everolimus is expected.

    Amprenavir

    Fosamprenavir

    Simultaneous application has not been studied, an increase in the concentration of everolimus is expected.

    Grapefruit, grapefruit juice, fruits of the carambola (tropical star), bitter orange and other products affecting the activity of cytochrome P450 and P-GP.

    Simultaneous application has not been studied, an increase in the concentration of everolimus is expected.

    Simultaneous use with the drug Afinitor® should be avoided.

    Powerful inductors CYP3A4

    Rifampicin

    AUC decreased by 63%

    Cmax decreased in 58%

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

    Glucocorticosteroids (for example, dexamethasone, prednisone, prednisolone)

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

    Carbamazepine

    Phenobarbital

    Phenytoin

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

    Efavirenz

    Nevirapine

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

    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 Cmax 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 Ki 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 CmOh Midazolam by 25% and the 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 Cmax and C2h 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. It is unlikely that an increase in the concentration of exemestane would affect the efficacy and safety of this drug.

    The combined application of octreotide and everolimus prolonged action results in increased Cmin octreotide, which has little effect on the clinical effect of everolimus in patients with metastatic 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 the drug Afinitor® should be done only under the supervision of a doctor who has experience with antitumor drugs.
    During therapy with the drug Atinitor® and at least 2 months after the use of reliable methods of contraception.
    Prior to initiation of treatment with the drug Afinitor® and periodically during therapy with the drug should monitor the kidney function, including measuring the concentration of blood urea nitrogen, protein in the urine or serum creatinine concentration, conduct a clinical blood test and determine the concentration of the drug in patients with SEGA.
    Before the start of treatment with the drug Afinitor® and periodically during therapy with the drug should monitor the concentration of blood glucose. An adequate control of the blood glucose concentration should be ensured before the beginning of treatment with the drug Afinitor®.
    Before the start of treatment with the drug Afinitor® and periodically during therapy with the drug should monitor the concentration of cholesterol and triglycerides.
    Before the start of treatment with the drug Afinitor® and periodically during the therapy with the drug should monitor the content of blood cells.
    Noninfectious pneumonitis is a class-specific side effect of rapamycin derivatives. When using the drug Afinitor®, there were also cases of development of noninfectious pneumonitis (including interstitial lung disease). In some cases, severe forms of the disease (rarely fatal) were observed. Diagnosis
    non-infectious pneumonitis should be assumed in patients with non-specific manifestations of such development on the part of the respiratory system as hypoxia, pleural effusion, cough or shortness of breath, as well as the exclusion using appropriate diagnostic studies infectious, neoplastic, and other causes of these symptoms.When performing differential diagnosis of noninfectious pneumonitis, opportunistic infections, for example, pneumocystis pneumonia, should be excluded.
    The patient should inform the attending physician of any new or increased respiratory symptoms. Patients who have only radiologic signs of noninfectious pneumonitis (in the absence or presence of minimal clinically significant symptoms) may continue treatment with the drug Afinitor® without changing the dose of the drug. 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 noninfectious pneumonitis, therapy with the drug Atinitor® 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 specific clinical conditions after treatment of pneumonitis, therapy with the drug can be resumed at a dose 50% lower than the initial dose (see Dosage and Administration).If the symptoms recur to grade 3, therapy with Afinitor® should be discontinued.
    A report was also received on the development of pneumonitis when taking 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.
    The drug Afinitor® has immunosuppressive properties and can promote the development of bacterial, fungal, viral or protozoal infections in patients, especially those caused by conditionally pathogenic microorganisms. Patients taking the drug Afinitor® described 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. Some of these infections were 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 use of 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 infectious diseases should be treated properly before using the drug 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 applied.
    Patients treated with the drug Afinitor® experienced ulceration of the oral mucosa, stomatitis and inflammation of the oral mucosa. In such cases, it is recommended to perform local therapy, however, mouth rinsing products containing alcohol, hydrogen peroxide, iodine and derivatives of thyme, because their use can worsen a patient's 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). Caution should be exercised with the simultaneous use of everolimus and moderate inhibitors of the isoenzyme CYP3A4 or inhibitors of P-GP.
    It is necessary to avoid simultaneous application of everolimus and powerful inducers of the isoenzyme CYP3A4.

    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 dangerous activities that require increased concentration.
    Form release / dosage:

    Tablets of 2.5 mg.

    Packaging:10 tablets in a blister pack. For 3 blisters together with instructions for use in a cardboard bundle.
    Storage conditions:

    In the original packaging at a temperature of no higher than 30 ° C.

    The drug should be stored 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:LP-001690
    Date of registration:03.05.2012 / 04.05.2017
    Expiration Date:Unlimited
    The owner of the registration certificate:Novartis Pharma AGNovartis Pharma AG Switzerland
    Manufacturer: & nbsp
    Representation: & nbspNOVARTIS PHARMA LLCNOVARTIS PHARMA LLC
    Information update date: & nbsp24.11.2017
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