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

Excipients: butyl hydroxytoluene 0.04 mg, 0.06 mg and 0.10 mg, lactose monohydrate 1.96 mg, 2.94 mg and 4.90 mg, hypromellose (type 2910) 18.00 mg, 27.00 mg and 45 , 00 mg, mannitol 108.00 mg, 162.00 mg and 270.00 mg, microcrystalline cellulose 62.50 mg, 93.75 mg and 156.25 mg, crospovidone 50.00 mg, 75.00 mg and 125.00 mg, magnesium stearate 5.00 mg, 7.50 mg and 12.50 mg, silicon dioxide colloid 2.50 mg, 3.75 mg and 6.25 mg.

Description:

Dispersible tablets 2 mg: round flat tablets with a bevel, from white to white with a yellowish hue, with an embossed "D2" on one side and "NVR" on the other.

Dispersible tablets 3 mg: round flat tablets with a bevel, from white to white with a yellowish shade of color, with embossing "D3" on one side and "NVR" on the other.

Dispersible tablets 5 mg: round flat tablets with a bevel, from white to white with a yellowish hue of color, with embossing "D5" on one side and "NVR" on the other.

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 PI3K7AKT-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, 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.

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

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 when taking the drug daily changes in proportion to the dose in the range of 5 to 10 mg. When taking everolimus once in a dose of 20 mg and higher, the increase FROM_maxoccurs 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 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 dispersible tablets, 3 mg) when taken with high and low fat food, the everolimus AUC decreased 11.7% and 29.5%, respectively, with a decrease 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).

Relative bioavailability of dispersible tablets

The area under the concentration-time curve (AUC_0-_∞) was equivalent when the dispersible tablets of everolimus are taken in the form of an aqueous suspension and when taking immediate release tablets of everolimus. The minimum values of the everolimus concentration, achieved the day after the drug administration, were comparable for both medicinal forms of everolimus. FROM_max everolimus was slightly lower when receiving dispersible tablets: from 64% to 80% of the values observed in the reception of immediate release tablets.

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%. 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 AUC_0-_τ were proportional to the dose of the drug when administered at doses of 5 to 10 mg per day and from 5 to 70 mg per week. The equilibrium state was achieved within two weeks with the daily administration of everolimus. FROM_max everolimus was proportional to the dose when the drug was administered in doses of 5 to 10 mg per day or per week. At doses of 20 mg per week and higher ascending FROM_max was less than a proportionate dose. 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 is increased 1.6, 3.3 and 3.6 times, respectively, if the liver function is mild (Class A Child-Pugh class), moderate severity (class In 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

- In patients with SEGA, the individual equilibrium minimum therapeutic concentration (C_min) 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 (C_min) 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 C_minEverolimus, 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:Subependymal giant-cell astrocytomas associated with tuberous sclerosis, with the impossibility of performing surgical resection of the tumor.

Contraindications:

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

- Expressed violations of liver function in patients with sub-ependymal giant cell astrocytomas (class C according to Child-Pugh classification).

- Pregnancy and the period of breastfeeding.

- Lactose intolerance, severe lactase deficiency or glucose-galactose malabsorption.

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), unless the benefits of taking the drug exceed the potential risk.

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.

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.

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.

The drug Afinitor® in the form of dispersible tablets is intended only for the treatment of patients with SEGA associated with tuberous sclerosis (TC), in conjunction with the control of the concentration of everolimus in the blood. Dispersible tablets rapidly dissolve in water to form a suspension that can be ingested with a syringe to receive suspensions or a small cup.

Treatment with the drug is carried out as long as the clinical effect remains and there are no signs of intolerable toxicity.

The preparation of Athenitor® in the form of dispersible tablets is intended for the preparation of a suspension, do not swallow the tablets whole, chew or grind. The suspension can be prepared in a suspension syringe or a small glass. It is necessary to ensure reception of the full prepared dose of the drug. Suspension should be taken immediately after preparation.

The prepared suspension should be disposed of if it has been stored for more than 60 minutes. To prepare the suspension, use only water.

Preparation of solution with a syringe

The required amount of dispersible tablets should be placed in a 10 ml syringe for suspensions.The maximum amount of the drug in a single syringe for the preparation of suspensions should not exceed 10 mg, if a higher dose is required, several syringes should be used. Collect about 5 ml of water and about 4 ml of air.

Fill the filled syringe into the beaker (piston down) for 3 minutes to dissolve the contents.

Before taking the drug, gently turn the syringe five times, holding the syringe tip up, remove excess air and immediately slowly insert the contents of the syringe into the patient's mouth.

To ensure the reception of a full dose, once again, draw the same volume of water and air into the syringe, rotating the syringe to wash the drug particles off the walls and insert the contents into the patient's mouth.

Preparation of a solution with a glass

The required amount of dispersible tablets should be placed in a small cup (maximum volume 100 ml) containing approximately 25 ml of water and left for 3 minutes. The maximum amount of the drug in one cup should not exceed 10 mg, if a higher dose is required, several cups should be used. Do not crush or break tablets.Immediately before taking the drug, gently mix the contents with a spoon. To ensure the reception of a full dose, take the same amount of water in the glass, rinse the remaining particles of the drug from the walls, mix the contents with the same spoon and give a drink to the patient.

Selection of the dose of the drug Afinitor® in patients with SEGA associated with tuberous sclerosis

The dose of the drug is determined based on the surface area of the body (BSA, m²), 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 dispersible tablets or tablets of the preparation Afinitor®.

Dispersible tablets of the preparation Afinitor® of various dosages can be combined to obtain the required dose, however, combining different dosage forms of the drug Afinitor® (for example, tablets and dispersible tablets) should not be used for this purpose.

Patients receiving everolimus therapy for SEGA should monitor the concentration of everolimus in the blood.

The concentration of everolimus in the blood should be determined approximately 2 weeks after the start of treatment. C_min the drug in the blood should be in the range of 5-15 ng / ml.

The dose may be increased to achieve a higher concentration within the therapeutic range in order to achieve optimal efficacy, taking into account the tolerability of the drug.

After initiation of therapy with the drug Athenitor®, the tumor volume of the CEGA should be measured 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.

After choosing the dose, you should monitor the concentration of everolimus in the blood plasma every 3-6 months in patients whose body surface area changes and 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, a dose of approximately 50% less than the previous dose is recommended (see Table 1).In patients receiving 2 mg of the drug Afinitor ® per day, it is possible to use the dosing regimen with taking the drug every other day.

Table 1 Recommendations for adverse events

Unwanted reaction	Degree of severity	Recommendations for dose modification and correction of adverse events²
Noninfectious pneumonitis	Degree 1	A dose change is not required.
	Absence of symptoms, except for radiographic signs	Condition monitoring.
	Degree 2
	Symptoms that do not affect daily life	Temporary cessation of therapy with the drug Afinitor®, exclusion of the infectious process, if necessary treatment glucocorticosteroids to reduce the severity of symptoms below grade 1.
		Resumption of treatment with the drug Afinitor® in a lower dose.
		Discontinuation of therapy if recovery does not occur within 3 weeks.
	Degree 3
	Symptoms that affect the daily life; use of oxygen therapy	Discontinuation of treatment with the drug Afinitor®, exclusion of the infectious process, if necessary, treatment with glucocorticosteroids to reduce the severity of symptoms below grade.
		Resumption of therapy with the drug Afinitor® from a lower dose.
		With the re-development of symptoms to grade 3 - discontinuation of therapy with the drug Afinitor®.
	Degree 4	The termination of treatment with the drug Afinitor®, an exception infectious process, if necessary treatment glucocorticosteroids.
Stomatitis	Degree 1 Symptoms of mild severity; a special diet is not required	The dose change is 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	Temporary cessation of admission to reduce the severity of symptoms to grade 1 and lower. Renewal of the drug with the same dose. When repeated occurrence of symptoms of grade 2 stomatitis - discontinuation of admission to a decrease in severity symptoms to grade 1 and below. Renewal of the drug from a lower dose. Treatment with analgesics for outdoor use application (benzocaine, butylaminobenzoate, tetracaine hydrochloride, menthol or phenol) with / without glucocorticosteroids for external applications³.
	Degree 3 Pronounced symptoms; ability to eat and liquids inside is limited	Temporary cessation of admission to reduce the severity of symptoms to grade 1 and lower. Renewal of the drug from a lower dose. Treatment with analgesics for external use (benzocaine, butylaminobenzoate, tetracaine hydrochloride, methanol or phenol) with or without glucocorticosteroids for external use³.
	Degree 4 Life-threatening condition	Discontinuation of treatment with the drug Afinitor® and the treatment of stomatitis with the use of appropriate therapy.
Other non-hematological toxicity (excluding metabolic disorders)	Degree 1	With tolerability of symptoms, a dose change is not required. Treatment by appropriate methods and monitoring of the condition.
	Power 2	With tolerability of symptoms, a dose change is not required. Treatment by appropriate methods and monitoring of the condition. If the symptoms are intolerant, temporarily stop treatment with the drug until the severity of the symptoms decreases to grade 1 and lower. Renewal of the drug from a lower dose.
	Power 3	Temporary discontinuation of the drug until the severity of symptoms is reduced to grade 1 and below. Treatment by appropriate methods and monitoring of the condition. Renewal of the drug from a lower dose. With the re-development of symptoms to grade 3 - discontinuation of therapy with the drug Afinitor®.
	Power 4	Discontinuation of the drug and treatment with appropriate methods.
Metabolic disorders (eg, hyperglycemia, dyslipidemia)	Degree 1	A dose change is not required if symptoms are tolerated. Treatment by appropriate methods and monitoring of the condition.
	Power 2	A dose change is not required if symptoms are tolerated. Treatment by appropriate methods and monitoring of the condition.
	Power 3	Temporary discontinuation of the drug. Renewal of the drug from a lower dose. Treatment by appropriate methods and monitoring of the condition
	Power 4	Discontinuation of the drug and treatment with appropriate methods.
¹Degrees of severity: 1 = mild 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. ³Avoid using drugs containing hydrogen peroxide, iodine and thyme derivatives in the treatment of stomatitis (can provoke an increase in ulceration in the oral cavity)

Treatment with the drug is carried out as long as the clinical effect remains and there are no signs of intolerable toxicity.

The preparation of Athenitor® in the form of dispersible tablets is intended for the preparation of a suspension, do not swallow the tablets whole, chew or grind.The suspension can be prepared in a suspension syringe or a small glass. It is necessary to ensure reception of the full prepared dose of the drug. Suspension should be taken immediately after preparation.

The prepared suspension should be disposed of if it has been stored for more than 60 minutes. To prepare the suspension, use only water.

Preparation of solution with a syringe

The required amount of dispersible tablets should be placed in a 10 ml syringe for suspensions. The maximum amount of the drug in a single syringe for the preparation of suspensions should not exceed 10 mg, if a higher dose is required, several syringes should be used. Collect about 5 ml of water and about 4 ml of air.

Fill the filled syringe into the beaker (piston down) for 3 minutes to dissolve the contents.

Before taking the drug, gently turn the syringe five times, holding the syringe tip up, remove excess air and immediately slowly insert the contents of the syringe into the patient's mouth.

Preparation of a solution with a glass

The required amount of dispersible tablets should be placed in a small cup (maximum volume 100 ml) containing approximately 25 ml of water and left for 3 minutes. The maximum amount of the drug in one cup should not exceed 10 mg, if a higher dose is required, several cups should be used. Do not crush or break tablets. Immediately before taking the drug, gently mix the contents with a spoon. To ensure the reception of a full dose, take the same amount of water in the glass, rinse the remaining particles of the drug from the walls, mix the contents with the same spoon and give a drink to the patient.

Selection of the dose of the drug Afinitor® in patients with SEGA associated with tuberous sclerosis

The dose of the drug is determined based on the surface area of the body (BSA, m²), calculated by the Dubois formula.

Dispersible tablets of the drug Afinitor® of various dosages can be combined to obtain the required dose,for this purpose, do not combine the different dosage forms of the drug Afinitor® (for example, tablets and dispersible tablets).

Patients receiving everolimus therapy for SEGA should monitor the concentration of everolimus in the blood.

The concentration of everolimus in the blood should be determined approximately 2 weeks after the start of treatment. C_min the drug in the blood should be in the range of 5-15 ng / ml.

The dose may be increased to achieve a higher concentration within the therapeutic range in order to achieve optimal efficacy, taking into account the tolerability of the drug.

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 (see Table 1). In patients receiving 2 mg of the drug Afinitor ® per day, it is possible to use the dosing regimen with taking the drug every other day.

Table 1 Recommendations for adverse events

Unwanted reaction	Degree of severity	Recommendations for dose modification and correction of adverse events²
Noninfectious pneumonitis	Degree 1	A dose change is not required.
	Absence of symptoms, except for radiographic signs	Condition monitoring.
	Degree 2
	Symptoms that do not affect daily life	Temporary cessation of therapy with the drug Afinitor®, exclusion of the infectious process, if necessary treatment glucocorticosteroids to reduce the severity of symptoms below grade 1.
		Resumption of treatment with the drug Afinitor® in a lower dose.
		Discontinuation of therapy if recovery does not occur within 3 weeks.
	Degree 3
	Symptoms that affect the daily life; use of oxygen therapy	Discontinuation of treatment with the drug Afinitor®, exclusion of the infectious process, if necessary, treatment with glucocorticosteroids to reduce the severity of symptoms below grade.
		Resumption of therapy with the drug Afinitor® from a lower dose.
		With the re-development of symptoms to grade 3 - discontinuation of therapy with the drug Afinitor®.
	Degree 4	The termination of treatment with the drug Afinitor®, an exception infectious process, if necessary treatment glucocorticosteroids.
Stomatitis	Degree 1 Symptoms of mild severity; a special diet is not required	The dose change is 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	Temporary cessation of admission to reduce the severity of symptoms to grade 1 and lower. Renewal of the drug with the same dose. When repeated occurrence of symptoms of grade 2 stomatitis - discontinuation of admission to a decrease in severity symptoms to grade 1 and below. Renewal of the drug from a lower dose. Treatment with analgesics for outdoor use application (benzocaine, butylaminobenzoate, tetracaine hydrochloride, menthol or phenol) with / without glucocorticosteroids for external applications³.
	Degree 3 Pronounced symptoms; ability to eat and liquids inside is limited	Temporary cessation of admission to reduce the severity of symptoms to grade 1 and lower. Renewal of the drug from a lower dose. Treatment with analgesics for external use (benzocaine, butylaminobenzoate, tetracaine hydrochloride, methanol or phenol) with or without glucocorticosteroids for external use³.
	Degree 4 Life-threatening condition	Discontinuation of treatment with the drug Afinitor® and the treatment of stomatitis with the use of appropriate therapy.
Other non-hematological toxicity (excluding metabolic disorders)	Degree 1	With tolerability of symptoms, a dose change is not required. Treatment by appropriate methods and monitoring of the condition.
	Power 2	With tolerability of symptoms, a dose change is not required. Treatment by appropriate methods and monitoring of the condition. If the symptoms are intolerant, temporarily stop treatment with the drug until the severity of the symptoms decreases to grade 1 and lower. Renewal of the drug from a lower dose.
	Power 3	Temporary discontinuation of the drug until the severity of symptoms is reduced to grade 1 and below. Treatment by appropriate methods and monitoring of the condition. Renewal of the drug from a lower dose. With the re-development of symptoms to grade 3 - discontinuation of therapy with the drug Afinitor®.
	Power 4	Discontinuation of the drug and treatment with appropriate methods.
Metabolic disorders (eg, hyperglycemia, dyslipidemia)	Degree 1	A dose change is not required if symptoms are tolerated. Treatment by appropriate methods and monitoring of the condition.
	Power 2	A dose change is not required if symptoms are tolerated. Treatment by appropriate methods and monitoring of the condition.
	Power 3	Temporary discontinuation of the drug. Renewal of the drug from a lower dose. Treatment by appropriate methods and monitoring of the condition
	Power 4	Discontinuation of the drug and treatment with appropriate methods.
¹Degrees of severity: 1 = mild 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. ³Avoid using drugs containing hydrogen peroxide, iodine and thyme derivatives in the treatment of stomatitis (can provoke an increase in ulceration in the oral cavity)

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 mg of the drug Afinitor ® per day, it is possible to use the dosing regimen with taking the drug every other day. Further dose reduction may be required in the development of severe and / or intolerable adverse events. The concentration of everolimus should be monitored 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-GP 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.When using the preparation of the Athenitor® simultaneously with the powerful inductors of the CYP3A4 isoenzyme (for example, antiepileptic drugs, including carbamazepine, phenobarbital and phenytoin), an increase in the dose of the drug Afinitor® may be required to achieve a therapeutic concentration of 5-15 ng / ml; should increase the daily dose of the drug Afinitor® 2 times and assess the tolerability of treatment with 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.

When using the preparation of Atinitor® simultaneously with powerful inductors of the CYP3A4 isoenzyme, an increase in the dose from 10 mg to 20 mg (10-20 mg per day) may be required on the basis of pharmacokinetic data in 5 mg increments per day. It is assumed that with this change in the dose of the drug Afinitor®, the AUC value will correspond to the AUC,observed without taking isoenzyme inducers, however, clinical data with a similar dose change in patients receiving potent inducers of the CYP3A4 isoenzyme are absent.

Transfer of the patient from one dosage form to another:

Do not combine two dosage forms of the drug Afinitor ®, to achieve the optimal therapeutic dose should use only one dosage form. When transferring a patient from one other dosage form to another, the nearest existing dosage should be selected and after 2 weeks the concentration of everolimus in the blood plasma should be measured.

Therapeutic monitoring of the concentration of everolimus in the blood in patients with SEGA.

In patients with SEGA, the concentration of everolimus in blood plasma should be monitored 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 concentration of everolimus should be carried out within 2 weeks after initiation of therapy,after any change in the dose or change in the dosage form of the drug or adherence to the therapy of inhibitors or inductors of the CYP3A4 isoenzyme or the appearance of signs of impaired liver function. C_min Everolimus in the blood should be in the range of 5-15 ng / ml. The dose should be titrated to the minimum therapeutic concentration, 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, while taking into account the tolerance of the drug.

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, except for patients with impaired liver function.

The drug Atinitor® is contraindicated in patients with SEGA associated with TC at the age of 18 years with violations of liver function class A, B, C according to the Child-Pugh classification.

The effectiveness and safety of the drug in children under 1 year is not established, and therefore the use of the drug in this category of patients is not recommended.

Patients ≥65 years of age

Correction of the dose is not required. Patients with impaired renal function No dosage adjustment is required.

Patients older than 18 years with impaired hepatic function

Violations 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).

Dysfunction 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).

Dysfunction of the liver of severe degree (class C according to the Child-Pugh classification): - 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). Titrate the dose to achieve a drug concentration in the range of 5 to 15 ng / ml. If the severity of the liver function is altered, the dose of the drug should be titrated. The dose may be increased to achieve a higher concentration within the therapeutic range in order to achieve optimal efficacy, taking into account the tolerability of the drug.

Instructions for use

The suspension is prepared using a syringe for oral administration, not included. For proper preparation of the suspension using a syringe, read carefully and carefully follow these instructions.

Important information

Each syringe for oral administration is suitable for preparing a suspension with a dosage of from 2 mg to 10 mg. If a higher dose is prescribed, it should be divided and repeated using the same syringe.

For cooking use only water (tap water or non-carbonated bottled).

After each use, rinse the syringe for oral administration with clean water; between use, store the syringe for oral administration dry.

The syringe for oral administration is intended only for the preparation of the ASSORTOR suspension for oral administration.

Preparation of a single dose of the suspension APHITER with a syringe for oral administration

Before you prepare the medicine, wash and dry your hands.

Take the syringe for oral administration by 10 ml and remove the plunger from it.

Remove the assigned amount of dispersible tablets (maximum 5 tablets 2 mg, 3 tablets 3 mg or 2 tablets 5 mg) and immediately place them in a syringe for oral administration.

Reinsert the plunger into the syringe and push it inward until it rests against the dispersible tablets.

Fill a drinking glass with water and take from it about 5 ml of water into the syringe for oral administration, slowly pulling the piston up.

Note: The volume of water in the syringe need not be exact. All dispersible tablets should be coated with water. If the dispersible tablets are left in the dry top of the syringe, gently tap on the syringe so that they move into the water.

Turn the syringe over and insert about 4 ml of air into the syringe, pulling the piston down.

Place the filled syringe in the beaker by placing it on the plunger (tipped up). Leave the syringe for 3 minutes to allow the dispersible tablets to dissolve. Proceed to the next stage only after 3 minutes have passed and the dispersible tablets completely disintegrate.

Carefully turn the syringe several times. Shake the syringe for oral administration is not allowed.

While holding the syringe for oral administration in the position with the tip up, gently remove excess air.

Immediately after this, slowly and accurately enter the contents of the syringe for oral administration into the patient's mouth.

Carefully remove the syringe from the patient's mouth.
Insert about 5 ml of water into the syringe, slowly pulling the piston up.

Turn the syringe over and insert about 4 ml of air into the syringe, pulling the piston down.

Rotating the syringe around the vertical axis, suspend the remaining particles of the drug.

While holding the syringe for oral administration in the position with the tip up, gently remove excess air.

Slowly and gently enter the entire contents of the syringe for oral administration into the patient's mouth.

Remove the plunger from the syringe and rinse all parts thoroughly with water. Keep them in a dry and clean place until next use.

Wash your hands.

Side effects:

In applying the drug most frequently reported adverse events (AEs) (frequency ≥10%, adverse events are listed in descending order of frequency of occurrence) were stomatitis, upper respiratory tract infections, amenorrhea, hypercholesterolemia, pazofaripgit, ugrevay rash, irregular menstrual cycles, sinusitis, otitis media and pneumonia.

The most frequent 3-4 cases of AH (frequency ≥1%) 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® with 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. The AIs are grouped according to the classification of organs and systems of the MedDRA organs, within each group are listed in order of decreasing frequency of occurrence.

Infectious and parasitic diseases: very often - upper respiratory tract infections, nasopharyngitis, sinusitis, otitis media, pneumonia; often - urinary tract infections, pharyngitis, subcutaneous fat inflammation, streptococcal pharyngitis, viral gastroenteritis, gingivitis, shingles; infrequently - a bronchitis of a virus etiology.

Immune system disorders: infrequently, hypersensitivity reactions. Disorders from the metabolism and nutrition: very often - hypercholesterolemia; often - hyperlipidemia, decreased appetite, hypertriglyceridemia, hypophosphatmia, hyperglycemia.

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

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

Disorders from the digestive system: very often - stomatitis (includes ulceration of the oral mucosa, lips and tongue, 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 (includes a 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.

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

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

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

Vascular disorders: often - increased blood pressure, lymphedema.

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

Laboratory and instrumental data: often - increasing the activity of lactate dehydrogenase (LDH), increasing the 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 purity of occurrence decreases):

hematologic: an increase in partial thromboplastin time, a decrease in hemoglobin concentration, a decrease in the absolute amount of neutrophils, leukopenia, lymphopenia, thrombocytopenia;

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

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

Severe (3-4 degrees) deviations included:

hematologic: often - a decrease in the absolute number of neutrophils, a decrease in the concentration of hemoglobin, an increase in partial thromboplastin time, lymphopsy; infrequently;

biochemical: often - hypophosphatemia, increased activity of alkaline phosphatase, hypertriglyceridemia, increased activity of ACT; infrequently - hypercholesterolemia, increased ALT activity, a decrease in potassium in the blood plasma, an increase in the concentration of blood glucose on an empty stomach.

Description of individual AEs according to clinical studies and with the use of everolimus in clinical practice in post-marketing period There have been cases of exacerbation of viral hepatitis B, including fatal cases. Exacerbation of infections is an expected phenomenon during periods of immunosuppression.

There were cases of renal failure (including with a legal 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 concomitant use with ACE inhibitors. and with the isolated application of everolimus.

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 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 the P-glycoprotein (P-GP pump), which allows the release of many drug compounds from the cells. 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.

Medicines (drugs) that can increase the concentration of everolimus in the blood:

The concentration of everolimus in the blood may increase with simultaneous use with drugs that are inhibitors of the isoenzyme CYP3A4 (decreased metabolism of everolimus) or the P-GP pump (decrease of efflux of everolimus from intestinal cells). Avoid simultaneous application of everolimus with potent inhibitors of the isoenzyme CYP3A4 or P-GP (including ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, clarithromycin, nefazodone, ritonavir, atazanavir, saquinavir, darunavir, indinavir, nelfinavir and other drugs with similar activity). Systemic bioavailability of everolimus increased significantly (increase in C_m_Oh and AUC, respectively, 4.1 and 15.3 times) in healthy volunteers with the co-administration of everolimus with ketoconazole, a potent inhibitor of the isoenzyme CYP3A4 and P-GP.

Caution should be exercised while using everolimus with moderate inhibitors of CYP3A4 (including erythromycin, verapamil, ciclosporin, fluconazole, diltiazem, amprenavir, fosamprenavir or aprepitant) or inhibitors of P-GP.

When used together with moderate inhibitors of the isoenzyme CYP3A4 or inhibitors of P-GP, the dose of the drug Afinitor® should be reduced.

Systemic bioavailability of the drug in healthy volunteers increased with simultaneous application with:

- erythromycin (a moderately active inhibitor of the isoenzyme CYP3A4 and P-GP, Stach and Averolimus AUC, respectively, increased 2 and 4.4 times)

-verapamil (moderately active inhibitor of the isoenzyme CYP3A4 and P-GP; Stach and AUC of everolimus increased respectively by 2.3 and 3.5 times),

-ciclosporin (substrate of the isoenzyme CYP3A4 and inhibitor of P-GP, Stach and AUC of everolimus increased 1.8 and 2.7 times, respectively).

Other moderate inhibitors of the isoenzyme CYP3A4 and P-GP that can increase the concentration of everolimus in the blood include certain antifungal agents (for example, fluconazole) and some blockers of "slow" calcium channels (for example, diltiazem).

There was no difference in C_min everolimus, applied in a daily dose of 5 or 10 mg, when applied together or without the substrates of the isoenzyme CYP3A4 and / or P-GP. Co-administration with weak inhibitors of the CYP3A4 isoenzyme together or without P-HP inhibitors did not affect C_min Everolimus, used in a daily dose of 5 or 10 mg.

Drugs that can reduce the concentration of everolimus in the blood:

The concentration of everolimus in the blood may decrease with the simultaneous use of drugs, which are inducers of the isoenzyme CYP3A4 (increasing metabolism of everolimus) or P-GP-pump (increase in the yield of everolimus from intestinal cells).

Avoid simultaneous application of everolimus with powerful inducers of the CYP3A4 isoenzyme or inductors of P-GP. If the use of the preparation of Afinitor® together with powerful inducers of the isoenzyme CYP3A4 or inductors of P-HP (eg rifampicin or rifabutin) is necessary, the dose of the drug should be increased.

In healthy volunteers who received previous therapy with rifampicin (600 mg / day for 8 days), subsequent application of everolimus in a single dose showed an almost 3-fold increase in the clearance of the latter and a decrease in C_m_Oh by 58% and AUC by 63%.

Other potent inducers of the isoenzyme CYP3A4 can also increase the metabolism of everolimus and decrease the concentrations of everolimus in the blood (for example, St. John's wort perforated glucocorticosteroids (for example, dexamethasone, prednisone, prednisolone), some anticonvulsants: carbamazepine, phenobarbital, phenytoin; drugs for HIV treatment: efavirenz, nevirapine).

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 isoenzyme CYP2D6-dextromethorphan. The mean steady-state Stach of Everolimus when taken orally at a dose of 10 mg per day or 70 mg per week is more than 12-36 times lower than K; 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 (substrate CYP3A4) results in an increase in C_m_Oh 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 combined use of everolimus and exemestane results in an increase in C_max and C_2h respectively by 45% and 71%. 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 use of everolimus and octreotide prolonged action leads to an increase in C_minoctreotide, which has little effect on the clinical effect of everolimus in patients with metastatic neuroendocrine tumors.

Other interactions that may affect the concentration of everolimus Avoid simultaneous application of everolimus with grapefruit, grapefruit juice, fruits of the carambola (tropical star), orange (bitter orange) and other products affecting the activity of cytochrome P450 and P-GP. 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 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.

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.

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. Kidney function in patients with additional risk factors should be closely monitored.

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®. Especially careful and more frequent glycemic control should be provided in patients with additional risk factors.

Before the start of treatment with the drug Afinitor® and periodically during the therapy with the drug should monitor the content of blood cells.

Before the start of treatment with the drug Afinitor® and periodically during therapy with the drug should monitor the concentration of cholesterol and triglycerides.

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. The diagnosis of noninfectious pneumonitis should be assumed in patients with the development of such nonspecific manifestations on the part of the respiratory organs, such as hypoxia, pleural effusion,cough or shortness of breath, and also with the exclusion of infectious, tumor and other causes of such manifestations by appropriate diagnostic tests. When conducting differential diagnosis of noninfectious pneumonitis, opportunistic infections, for example, pneumocystis pneumonia, should be excluded. Patients should be informed to the treating 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.

When developing severe symptoms (grade 3 or 4) of noninfectious pneumonitis, therapy with the drug Atinitor® should be temporarily stopped until the severity of symptoms is reduced to grade 1 and below.In clinical trials, the incidence of this complication was also observed with the use of reduced doses of the drug Afinitor®. 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). When re-occurrence of symptoms of severity 3 should consider stopping therapy with the drug. With the severity of symptoms, 4 therapy with the drug Atinitor® should be discontinued.

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 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 use of the drug Afinitor®, be attentive to the symptoms and signs of infections and, when they occur, 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 initiated.

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, mouth rinsing agents containing alcohol, hydrogen peroxide, iodine and thyme, because 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).

In the case of the use of the drug Afinitor® in patients under the age of 18, all recommended by the local calendar should be carried outvaccination with antiviral vaccination.

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 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 are dispersible for 2, 3 and 5 mg.

Packaging:

For 10 tablets per blister from PA / Al / PVC.

For 3 blisters together with instructions for use in a cardboard bundle.

Storage conditions:

In dry, dark place at a temperature of no higher than 30 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use the drug after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002288