Instruction for use: Afinitor

Dosage form: Tablets; Tablets, dispersible

Active substance: Everolimusum

ATX

L01XE10 Everolimus

Pharmacological group:

Antitumor agent - a protein kinase inhibitor [Antitumor agents - protein kinase inhibitors]

The nosological classification (ICD-10)

C64 Malignant neoplasm of kidney, other than renal pelvis: Wilms tumor; Kidney Cancer; Metastatic Renal Cell Carcinoma; Renal carcinoma; Inoperable kidney carcinomas; Metastatic kidney carcinoma; Metastatic Renal Cell Carcinoma; Wilms tumor; Wilms swelling; Adenomyosarcoma; Adenomyocystosarcoma; Adenosarcoma of the kidney; Kidney Cancer; Common renal cell carcinoma; Nephroblastoma; Nephroma; Embryonal nephroma; Recurrent carcinoma of the kidney; Birch-Hirschfeld Tumor; Common renal cell carcinoma; Tumors of the kidney

Composition and release form

Tablets - 1 table.

active substance: Everolimus (stabilized with 0.2% butylhydroxytoluene) 5 mg; 10 mg

Auxiliary substances: lactose anhydrous - 143.75 / 287.5 mg; Crospovidone - 50/100 mg; Hypromellose - 45/90 mg; Lactose monohydrate - 4.9 / 9.8 mg; Magnesium stearate - 1.25 / 2.5 mg; Butylhydroxytoluene 0.1 / 0.2 mg

In the blister 10 pcs .; In a pack of cardboard 3, 6 and 9 blisters.

Description of dosage form

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

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

Pharmachologic effect

Mode of action - Antitumor.

Pharmacodynamics

The active substance of the drug Afinitor ® - everolimus - is an inhibitor of proliferative signal transmission.

Everolimus is a selective inhibitor of serine-threonine kinase mTOR (a target of rapamycin in mammals) that specifically affects the mTORC1 complex of the signal-converting mTOR kinase and the regulatory raptor protein (regulatory associated protein of mTOR). The mTORC1 complex is an important regulator of protein synthesis in the distal part of the PI3K / AKT-dependent cascade, the regulation of which is disrupted in most human cancers. Everolimus manifests its activity through high affinity interaction with intracellular receptor protein FKBP12. Complex FKBP12-everolimus binds to mTORC1, inhibiting its ability to transmit signals.

The mTORC1 signaling function is realized by modulating the phosphorylation of distal effector cells, of which the most fully characterized translational regulators are the ribosomal protein S6 (S6K1) kinase and the eukaryotic cell elongation factor 4E-B (4E-BP). The disruption of the function of S6K1 and 4E-BP1 due to inhibition of mTORC1 disrupts the translation of the encoded mRNAs of the main 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).

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 advanced and / or metastatic renal cell carcinoma, progressing after previous therapy with tyrosine kinase inhibitors and / or cytokines, everolimus significantly reduced the risk of disease progression and death of patients by 67%. When using the drug, the survival rate of patients without disease progression was 4.9 months. Within 6 months in 36% of patients receiving everolimus, there was no progression of the disease. Using everolimus can significantly improve the quality of life of patients (assessed the impact of the symptoms of the disease on various areas of the patient's life).

Pharmacokinetics

Suction

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 Cmax with the intake of 5 to 10 mg of the drug daily or weekly changes in proportion to the dose. When taking everolimus in doses of 20 mg per week or more, the increase in Cmax occurs less than proportionally to the dose, but the AUC values increase in proportion to the dose when taken from 5 mg to 70 mg of the drug. When taking everolimus at a dose of 10 mg, a high-fat diet reduced the AUC and Cmax of the drug by 22 and 54%, respectively. Low-fat foods reduced AUC and Cmax by 32% and 42%, respectively. However, eating did not have a significant effect on the elimination of the drug.

Distribution

The percentage of the everolimus 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 approximately 20% of its amount in the blood at the substance concentrations recorded in the blood of cancer patients taking everolimus at 10 mg per day. Binding to plasma proteins is approximately 74% in healthy subjects and in patients with moderately impaired liver function.

In experimental studies, it was shown that after intravenous administration, the penetration of everolimus through the BBB is dose dependent nonlinearly, which implies saturation of the BBB pump, which ensures that the drug enters the brain tissue from the blood. Penetration of everolimus through the BBB has also been demonstrated in animals that received the drug inside.

Metabolism

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

Excretion

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

Pharmacokinetics in an equilibrium state

After daily or weekly administration of everolimus, the values of AUC0-t were proportional to the dose of the drug when administered at doses of 5 to 10 mg per day and 5 to 70 mg per week. The steady-state (equilibrium) state was achieved within two weeks with the daily administration of everolimus. Cmax everolimus was proportional to the dose when the drug was used at doses of 5 to 10 mg per day or per week. At doses of 20 mg per week and higher, the increase in Cmax was less than a proportional dose. Tmax in the blood plasma was 1-2 hours. With the daily administration of everolimus upon reaching the equilibrium state, there was a significant correlation between the AUC0-t value and the concentration of the drug in the blood before taking the next dose. T1 / 2 of everolimus is about 30 h.

Pharmacokinetics in selected groups of patients

Patients with impaired liver function. The mean AUC in patients with moderate hepatic impairment (class B according to the Child-Pugh classification) was twice as large as in patients with normal liver function. There was a positive correlation between the AUC value on the one hand and the serum bilirubin concentration and the lengthening of the PV on the other. Between the values of AUC and serum albumin concentration, a negative correlation was found. The effect of severe liver function disorders (class C according to Child-Pugh classification) on the pharmacokinetics of everolimus has not been studied.

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. 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 the drug in children and adolescents with tumors under the age of 18 years has not previously been studied.

Patients aged ≥65 years. 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.

The influence of race. The clearance of everolimus (CL / F) after ingestion of the medication in the faces of Caucasoid and Mongoloid races with cancer, with similar liver function, 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 the Caucasoid race.

Effect of exposure on efficiency. There was some correlation between a decrease in the phosphorylation of 4E-BP1 in the tumor tissue and the mean Cmin of everolimus in the blood in a steady-state (equilibrium) state after a daily intake of 5 or 10 mg of the drug. Additional data suggest that a decrease in phosphorylation of S6 kinase is very sensitive to inhibition of mTOR under the influence of everolimus. The suppression of phosphorylation of the translation initiation factor elF-4G was complete for all Cmin values of everolimus detected in the blood with daily administration of the drug at a dose of 10 mg.

Indication of the drug Afinitor

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

Contraindications

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

Expressed violations of liver function (class C according to Child-Pugh classification) (lack of data on efficacy and safety);

Pregnancy and the period of breastfeeding;

Children's age and adolescence under 18 years (lack of data on efficacy and tolerability).

Avoid simultaneous application of everolimus with strong inducers of the CYP3A4 isoenzyme or P-glycoprotein inducers (P-GP pump).

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

Afenitor® should not be used in patients with rare hereditary disorders associated with intolerance to galactose, severe lactase deficiency, or glucose-galactose malabsorption.

Since rapamycin derivatives, including Afinitor®, can slow the wound healing process, care should be taken when prescribing the drug to patients before surgery.

Side effects

When using the drug, the most common adverse events (frequency ≥10%) were stomatitis, skin rash, fatigue, asthenia, diarrhea, anorexia, nausea, mucositis, vomiting, cough, peripheral edema, infections, dry skin, nosebleeds, Itching and shortness of breath. The most frequent adverse events (AE) of 3-4 degree of severity (frequency ≥2%) were: infections, stomatitis, fatigue and pneumonitis.

When using the drug, the frequency of withdrawal from therapy due to the development of AEs was 6%. In clinical trials, the majority of AEs that developed as a result of the drug and placebo had 1 or 2 severity.

The 3rd, 4th or 4th degree of severity was observed in 39% of patients taking Athenitor ®.

Below are the AEs that occurred with the use of Afinitor® (10 mg per day) with the frequency of their occurrence: very often (≥1/10), often (≥1 / 100 and <1/10), sometimes (≥1 / 1000 and <1/100), rarely (≥1 / 10000 and <1/1000), very rarely (<1/10000), incl. Individual messages.

On the part of the organs of hematopoiesis: very often - lymphocytopenia; Anemia, thrombocytopenia, neutropenia.

From the nervous system: very often - headache; Often - insomnia; Sometimes loss of taste sensitivity.

From the side of the organ of vision: often - conjunctivitis, swelling of the eyelids.

From the CVS: often - arterial hypertension, sometimes - congestive heart failure.

From the respiratory system: very often - cough, pneumonitis, epistaxis, dyspnea; Often hemoptysis.

From the digestive system: very often - anorexia, stomatitis, diarrhea, nausea, vomiting, changes in taste; Often - dry mouth, abdominal pain, dysphagia, dyspepsia.

From the skin and skin appendages: very often - rash, dry skin, itching; Often - palmar-plantar syndrome, erythema.

From the urinary system: often - increased urination in the daytime (1.8%).

On the part of the endocrine system: often - exacerbation of existing diabetes mellitus; Sometimes - newly diagnosed diabetes mellitus.

Metabolic disorders: very often - increasing the concentration of cholesterol, triglycerides, glucose, creatinine, increasing the activity of AST, ALT, reducing the concentration of phosphorus in the blood; Often - an increase in the concentration of bilirubin in the blood.

Other: very often - increased fatigue, asthenia, peripheral edema, attachment of secondary infections; Often - dehydration, pain in the chest; Sometimes - slow healing of wounds, fever, loss of body weight.

There were also isolated cases of bleeding of different localization of the 1st degree of severity.

When everolimus was used, there were cases of development of hypersensitivity, manifested by anaphylactic reactions, dyspnea, flushing of the face, chest pain or angioneurotic edema (eg, swelling of the respiratory tract and tongue without or with respiratory failure).

In clinical studies, the use of the drug marked the development of hyperglycemia.

In clinical studies with the use of the drug, there have been cases of exacerbation of viral hepatitis B, including death. Exacerbation of infections is an expected phenomenon during periods of immunosuppression.

Interaction

Everolimus is a substrate of CYP3A4, as well as a substrate and moderately active inhibitor of P-glycoprotein (P-GP-pump), which provides the isolation of many drug compounds from cells. Therefore, the substances that interact with CYP3A4 and / or P-HP may affect the absorption and subsequent excretion of everolimus.

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

Drugs that can increase the concentration of everolimus in the blood

The concentration of everolimus in the blood can be increased when used together with preparations that inhibit the isoenzyme CYP3A4 (decrease the metabolism of everolimus) or the P-GP pump (decrease in the isolation of everolimus from intestinal cells). Avoid simultaneous use of everolimus with strong inhibitors of 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 (an increase of Cmax and AUC of the drug was 4.1 and 15.3 times, respectively) in healthy subjects with co-administration of everolimus with ketoconazole, a potent inhibitor of CYP3A4 and P-GP.

Caution should be exercised while using everolimus with moderate inhibitors of CYP3A4 (including erythromycin, verapamil, cyclosporine, fluconazole, diltiazem, amprenavir, fosamprenavir or aprepitant) or P-GP. When used with moderate inhibitors of CYP3A4 or P-GP, the dose of Afinitor® should be reduced.

Systemic bioavailability of the drug in healthy subjects increased with simultaneous use with:

- erythromycin (moderately active inhibitor of CYP3A4 and P-GP, Cmax and AUC of everolimus increased 2 and 4, 4 times, respectively);

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

- cyclosporin (substrate CYP3A4 and moderate inhibitor of P-GP, Cmax and AUC of everolimus increased 1.8 and 2.7 times, respectively).

Other moderate inhibitors of CYP3A4 and P-GP that can increase the concentration of everolimus in the blood include certain antifungal agents (eg, fluconazole) and some CCBs (eg, diltiazem).

Drugs that can reduce the concentration of everolimus in the blood

The concentration of everolimus in the blood may decrease when applied together with drugs that are inducers of the isoenzyme CYP3A4 (increasing the metabolism of everolimus) or the P-GP pump (increasing the release of everolimus from intestinal cells). Avoid simultaneous application of everolimus with strong inducers of CYP3A4 or inductors of P-GP. If the use of Afinitor® together with strong inducers of 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 rifampicin therapy (600 mg / day for 8 days), with the subsequent application of everolimus in a single dose, there was an almost 3-fold increase in the clearance of the latter and a decrease in Cmax by 58% and AUC by 63%.

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

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

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

In vitro, everolimus competitively inhibited the metabolism of the substrate CYP3A4-cyclosporin and was a mixed inhibitor of the substrate CYP2D6-dextromethorphan. The mean steady-state Cmax of everolimus when taken internally at a dose of 10 mg per day or 70 mg per week is more than 12 to 36 times lower than the Ki values of the inhibitory effect compound in vitro on CYP3A4 and CYP2D6. Therefore, the effect of everolimus in vivo on the metabolism of substrates CYP3A4 and CYP2D6 is unlikely.

Other interactions that may affect the concentration

It should avoid the simultaneous use of Afinitor® with grapefruit, grapefruit juice and other products that affect the activity of cytochrome P450 and P-GP.

Vaccination

Immunosuppressants may influence the response during vaccination; Against the backdrop of treatment with Afinitor® vaccination may be less effective. Use of live vaccines should be avoided.

Dosing and Administration

Inside. Afinitor® should be taken once a day every day at the same time (preferably in the morning) on an empty stomach or after a small amount of food that does not contain fat. Tablets should be swallowed whole, washed down with a glass of water, they cannot be chewed or crushed.

Treatment with the drug is carried out as long as the clinical effect remains.

The recommended dose of Afinitor® is 10 mg once a day. In case of severe and / or intolerable adverse events, reduce the dose of Afinitor® to 5 mg / day and / or temporarily discontinue therapy with the drug.

When applied simultaneously with moderate inhibitors of CYP3A4 and P-GP, the dose of Afinitor® should be reduced to 5 mg / day. With the development of severe and / or intolerable adverse events in patients receiving the drug concomitantly with moderate inhibitors of CYP3A4 and P-GP, the dose of Afinitor® should be reduced to 5 mg / day every other day.

With the simultaneous use of everolimus with strong inducers of CYP3A4 or inducers of P-GP, the dose of the drug can be increased by the doctor's decision gradually from 10 mg / day to 20 mg / day (the incremental increment of 5 mg).

It is assumed that when an Atfinitor® dose of 20 mg is administered simultaneously with strong inducers of CYP3A4 or P-GP, there will be no decrease in the AUC of the drug (however, this is not confirmed by clinical data). If treatment with strong inducers CYP3A4 or P-GP is stopped, the Afinitor® should be administered at the dose in which the patient took it before treatment with strong CYP3A4 or P-GP inducers.

Patients aged ≥65 years: dose adjustment is not required.

Patients with impaired renal function: dosage adjustment is not required.

Patients with impaired hepatic function: in patients with impaired liver function of moderate degree (class B according to Child-Pugh classification), the dose of Afinitor® should be reduced to 5 mg per day.

Overdose

No cases of drug overdose have been reported.

Treatment: in case of an overdose of 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.

Special instructions

Treatment with Afinitor® should be done only under the supervision of a doctor who has experience with antitumor drugs.

During the therapy with Afinitor® and at least 2 months afterwards, reliable methods of contraception should be used.

Before the start of treatment with Afinitor® and periodically during therapy with the drug, kidney function should be monitored, including measurements of blood urea nitrogen concentration or serum creatinine content and a clinical blood test.

Non-infectious pneumonitis is a class-specific side effect of rapamycin derivatives. When Afinitor® was used, there were also cases 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 non-specific manifestations from the respiratory organs as hypoxia, pleural effusions, coughing or shortness of breath, and also by excluding, through appropriate diagnostic tests, the infectious, tumor and other causes of such manifestations. Patients should be informed to the attending physician of any new or increased respiratory symptoms. Patients who have only radiologic signs of noninfectious pneumonitis (in the absence of clinically significant symptoms) may continue treatment with 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, SCS can be used. Treatment with the drug can be resumed at a dose of 5 mg / day. With the development of severe symptoms of non-infectious pneumonitis, therapy with Afinitor® should be discontinued. Depending on the specific clinical conditions after the treatment of pneumonitis, therapy with the drug can be resumed at a dose of 5 mg / day.

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. In patients taking Afinitor®, local and systemic infections have been described, including pneumonia, other bacterial infections, and fungal infections such as aspergillosis or candidiasis, and viral infections, including exacerbation of viral hepatitis B. Some of these infections have been severe Development of respiratory or hepatic insufficiency) and sometimes led to a lethal outcome. Patients should be informed of the increased risk of infections with the use of Afinitor®, be sensitive to the symptoms and signs of infections and, if prompted, seek medical advice.

Patients with fungal infections should be treated appropriately before the appointment of Afinitor®.

In patients treated with Afinitor®, ulceration of the oral mucosa, stomatitis and inflammation of the oral mucosa were observed. In such cases, local therapy is recommended, but the use of mouth rinsing products containing alcohol or hydrogen peroxide should be avoided, since their use can worsen the condition. Antifungal agents should be used only if confirmed fungal infection.

Prior to treatment with Afinitor® and periodically during therapy with the drug should monitor the blood glucose in the fasting serum. Prior to the start of treatment with Afinitor®, optimal control of blood glucose levels should be ensured.

Influence on ability to drive vehicles and work with mechanisms

Studies of the influence of the Aienitor® on the ability to drive and work with mechanisms have not been carried out.

Conditions of supply of pharmacies

On prescription

Storage conditions of the drug Afinitor

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

Keep out of the reach of children.

Shelf life of the drug Afinitor

3 years.

Do not use after the expiry date printed on the package.