Affinitor
Afinitor: instructions for use and reviews
- 1. Release form and composition
- 2. Pharmacological properties
- 3. Indications for use
- 4. Contraindications
- 5. Method of application and dosage
- 6. Side effects
- 7. Overdose
- 8. Special instructions
- 9. Application during pregnancy and lactation
- 10. Use in childhood
- 11. In case of impaired renal function
- 12. For violations of liver function
- 13. Use in the elderly
- 14. Drug interactions
- 15. Analogs
- 16. Terms and conditions of storage
- 17. Terms of dispensing from pharmacies
- 18. Reviews
- 19. Price in pharmacies
Latin name: Afinitor
ATX code: L01XE10
Active ingredient: everolimus (everolimus)
Producer: Novartis Pharma Stein AG (Switzerland)
Description and photo update: 2019-19-08
Prices in pharmacies: from 88 250 rubles.
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Afinitor is an antitumor drug, an inhibitor of protein tyrosine kinase.
Release form and composition
The affinitor comes in the following forms:
- dispersible tablets: flat, round, from white to white with a yellowish sheen, beveled; on one side there is an embossing "D2", "D3" or "D5" (for tablets 2 mg, 3 mg or 5 mg, respectively), on the other - NVR (10 pieces in blisters, in a cardboard box 3 blisters);
- tablets: oblong, flat, from white to white with a yellowish sheen, beveled; on one side there is embossing LCL, "5" or UHE (for 2.5 mg, 5 mg or 10 mg tablets, respectively), on the other - NVR (2.5 mg tablets - 10 pieces in blisters, in a cardboard box 3 blisters; tablets 5 mg and 10 mg - 10 pieces in blisters, in a cardboard box of 3, 6 or 9 blisters).
Composition of 1 dispersible tablet:
- active substance: everolimus - 2 mg, 3 mg or 5 mg;
- auxiliary components: mannitol, colloidal silicon dioxide, butylhydroxytoluene, microcrystalline cellulose, lactose monohydrate, magnesium stearate, hypromellose, crospovidone.
Composition of 1 tablet:
- active substance: everolimus - 2.5 mg, 5 mg or 10 mg;
- auxiliary components: crospovidone, lactose monohydrate, butylhydroxytoluene, anhydrous lactose, magnesium stearate, hypromellose.
Pharmacological properties
Pharmacodynamics
Everolimus inhibits proliferative signaling. This substance selectively inhibits the target of mammalian rapamycin, the serine-threonine protein kinase mTOR, by specifically affecting the mTORC1 signal-converting mTOR kinase and regulatory raptor protein complex. The mTORC1 complex regulates protein synthesis in the distal part of the PI3K7AKT-dependent cascade, the normal function of which is impaired in the development of most malignant tumors. The active ingredient of the drug Afinitor has a high-affinity interaction with the intracellular receptor protein FKBP12. The signaling function of the latter is inhibited due to the connection between the RKVR12-everolimus and mTORC1 complexes.
The ability of mTORC1 to transmit signals is realized by modulating the phosphorylation of distal effectors: ribosomal protein kinase S6 (S6K1), eukaryotic cell initiation factor, and 4E-binding protein (4E-BP1). As a result of mTORC1 inhibition, the function of proteins 4E-BP1 and S6K1 is impaired and, accordingly, the translation of the main proteins encoded by mRNA and regulating the cell cycle, glycolysis and adaptation of cells to low oxygen levels (hypoxia). As a result, tumor growth and expression of hypoxia-induced factors (for example, the transcription factor HIF-1) are suppressed, which reduces the expression of factors (for example, vascular endothelial growth factor) that enhance angiogenesis - the process of formation of new blood vessels in a tumor. Signaling through mTORC1 is regulated by tumor suppressor genes - the tuberous sclerosis genes TSC1 and TSC2. In the presence of tuberous sclerosis, which is a genetically determined disease, inactivating mutations in both or one of the TSC1 and TSC2 genes cause the formation of multiple hamartomas with different localization.
Everolimus is an active inhibitor of the growth and proliferation of fibroblasts, tumor, endothelial and smooth muscle tissues of blood vessels.
In subependymal giant cell astrocytomas associated with tuberous sclerosis, after six months of everolimus therapy, patients showed a statistically significant decrease in tumor volume (in 75% of patients, tumor volume reduction was at least 30%, in 32% of patients - at least 50%). As a result of taking the drug, the patients had no new foci, no increased hydrocephalus and no signs of increased intracranial pressure, and there was no need for surgical treatment of subependymal giant cell astrocytomas. The sustained efficacy of everolimus has been confirmed during long-term follow-up of patients with subependymal giant cell astrocytomas associated with tuberous sclerosis.
Pharmacokinetics
Absorption
After oral administration of 5–70 mg of the drug (on an empty stomach or with a small amount of low-fat food), the time to reach the maximum concentration (C max) in the blood is from 1 to 2 hours. With max at daily intake of Afinitor changes in proportion to the dose taken in the range of 5-10 mg. In the case of a single dose of everolimus at a dose of 20 mg and above, the increase in its maximum concentration occurs to a lesser extent, while the values of the area under the pharmacokinetic curve (AUC) when taking 5–70 mg of the drug increase in proportion to the dose.
After oral administration of 10 mg everolimus together with food with a high fat content, C max and AUC of the drug decreased by 54% and 22%, respectively.
Diet with a low fat diet resulted in a decrease in C max and AUC by 42% and 32%, respectively. In healthy volunteers, with a single dose of 9 mg everolimus (in the form of dispersible tablets of 3 mg) together with food with low and high fat content, C max decreased by 50.2% and 59.8%, respectively, and the AUC decreased, respectively, by 29.5% and 11.7%.
Indicators of drug elimination within 1 day did not have a significant relationship with food intake.
Relative bioavailability of dispersible tablets
In the case of oral administration of dispersible tablets in the form of an aqueous suspension and tablets with an immediate release of everolimus, the area under the concentration-time curves was equivalent. The minimum value of the concentration of everolimus, reached 1 day after its administration, was comparable for both of these dosage forms. When using dispersible tablets, the C max of everolimus was slightly lower (in the range of 64–80% of the values typical for taking immediate-release tablets).
Distribution
In patients with cancer who took everolimus at a dose of 10 mg per day, the concentration of the substance in plasma was about 20% of its concentration in whole blood. The percentage ratio of the content of everolimus in the blood to its content in the blood plasma is dependent on the content of the compound in the range of 5–5000 ng / ml and varies in the range of 17–73%. In both healthy volunteers and patients with moderate liver dysfunctions, about 74% of the drug binds to plasma proteins.
In the course of experimental studies, it was shown that as a result of intravenous administration of everolimus, the dose dependence of its penetration through the blood-brain barrier is nonlinear. This fact indicates the alleged saturation of the blood-brain barrier pump, which ensures the entry of the active substance into the brain tissue. Penetration through the blood-brain barrier is also evidenced by data from animal studies that received everolimus orally.
Metabolism
Everolimus is a substrate of P-glycoprotein and CYP3A4 isoenzyme. After oral administration of Afinitor, everolimus circulates in the blood mainly unchanged. There are six major metabolites of everolimus, including three monohydroxylated metabolites, a phosphatidylcholine conjugate, and two open-ring hydrolytic conversion products. The activity of these metabolites is approximately 100 times lower than that of everolimus. It is generally accepted that the main general pharmacological activity of everolimus is due to the action of an unchanged compound.
Withdrawal
After a single injection of radiolabeled everolimus, 80% of the radioactivity is determined in the feces, and 5% is excreted by the kidneys. In feces and urine, unchanged everolimus was not detected.
Equilibrium pharmacokinetics
With daily or weekly intake, the AUC values of 0-τ everolimus are proportional to the dose taken in the range of 5-10 mg per day or 5-70 mg Afinitor per week. When taken daily, the equilibrium state is reached within 2 weeks. When using everolimus at a dose of 5-10 mg per day or per week, C max is proportional to the dose. When taking everolimus at a dose of 20 mg per week and above, C max increases to a lesser extent. The time to reach C max in blood plasma is from 1 to 2 hours. In the case of daily intake of everolimus after reaching equilibrium, there is a significant correlation between the AUC value 0-τand the content of everolimus in the blood before using the next dose of the drug. The half-life is approximately 1.25 days.
Pharmacokinetics in selected patient groups
In case of impaired liver function, the increase in the systemic exposure of Afinitor is:
- in patients with mild liver dysfunction (class A according to the Child - Pugh classification) - 1.6 times;
- in patients with moderate liver dysfunction (class B according to the Child - Pugh classification) - 3.3 times;
- in patients with severe hepatic dysfunction (class C according to the Child-Pugh classification) - 3.6 times.
In case of impaired liver function, dose adjustment of everolimus is required.
In post-transplant renal dysfunction (CC 11–107 ml / min) in patients after organ transplantation, the pharmacokinetics of everolimus did not change. In progressive solid tumors, no significant dependence of the clearance of everolimus (CL / F) on the clearance of creatinine (CC 25–178 ml / min) was found.
Patients under the age of 18 years at subependymal giant cell astrocytomas (SEAGA) value of individual equilibrium everolimus minimum therapeutic concentration (C min) was directly proportional to the daily dose and ranged from 1.35 to 14.4 mg / m 2. Patients with SEAGA under the age of 18 years, the geometric mean C min, normalized to the received dose (in mg / m 2), was significantly lower compared with adult patients, which may indicate an increased clearance of everolimus in children.
In patients aged 27–85 years after oral administration of Afinitor, a significant effect of age parameters on the clearance of everolimus (with CL / F from 4.8 to 54.7 l / h) was not revealed.
Influence of race
After oral administration of the drug, the clearance of everolimus (CL / F) did not differ in Mongoloid and Caucasian races with similar liver function.
According to the results of a population pharmacokinetic analysis after organ transplantation in the Negroid race, the clearance of everolimus (CL / F) (when taken by mouth) averaged 20% more than in the Caucasian race.
Effect of exposure on efficiency
With the daily intake of everolimus at a dose of 5 to 10 mg, a definite correlation was recorded between a decrease in 4E-BP1 phosphorylation in tumor tissues and C min in the blood in an equilibrium state.
There is additional evidence that the decrease in S6 kinase phosphorylation is highly sensitive to the inhibition of serine-threonine protein kinase mTOR by everolimus. Recorded by the complete suppression of phosphorylation of the translation initiation factor eIF-4G over the entire range of values C min everolimus blood Afinitora when receiving a dose of 10 mg on a daily basis.
In patients with subependymal giant cell astrocytomas, with a twofold increase in C min, the tumor size decreases by 13%, while a 5% reduction in tumor size is considered statistically significant.
Indications for use
- subependymal giant cell astrocytomas (SEGA) associated with tuberous sclerosis (TS) in persons over three years old (if surgical resection of the tumor is not possible);
- metastatic and / or advanced neuroendocrine tumors of the lung, gastrointestinal tract and pancreas;
- angiomyolipoma of the kidney associated with tuberous sclerosis (unless immediate surgery is required);
- metastatic and / or advanced renal cell carcinoma (in case of ineffectiveness of anti-angiogenic treatment);
- hormone-dependent advanced breast cancer in post-menopausal women after prior endocrine treatment (in combination with an aromatase inhibitor).
According to the instructions, Afinitor in the form of dispersible tablets is used only for the treatment of patients with SEGA associated with TS.
Contraindications
Absolute:
- liver dysfunctions (Child-Pugh class A, B and C) in children and adolescents 3–18 years old with SEGA;
- liver dysfunction (Child-Pugh class C) in adult patients with SEGA;
- children's age up to 3 years (with SEGA), up to 18 years (other indications);
- period of pregnancy and lactation;
- simultaneous use with strong inducers of P-glycoprotein or inducers of the CYP3A4 isoenzyme;
- hypersensitivity to any of the components of the drug or other derivatives of rapamycin.
Relative (Afinitor is used with caution):
- rare hereditary disorders associated with galactose intolerance, glucose-galactose malabsorption or severe lactase deficiency;
- surgical interventions (since the drug can slow down the wound healing process);
- simultaneous use with moderate P-glycoprotein inhibitors or CYP3A4 inhibitors.
Instructions for the use of Afinitor: method and dosage
Afinitor is taken orally once a day at the same time (preferably in the morning). The tablets are taken on an empty stomach or after a light snack, in which there are no fats.
Dispersible tablets Afinitor are intended for suspension preparation and should not be chewed, crushed or swallowed whole. The suspension is prepared in a small glass or in a special suspension syringe, using water for dilution, and taken immediately after preparation.
Afinitor tablets are swallowed whole with a glass of water. If the patient, for health reasons, cannot swallow the pill whole, it is recommended to dissolve it in 30 ml of water immediately before use, drink the resulting solution, then rinse the glass with 30 ml of water again and drink the solution (this ensures that the full dose is taken).
Treatment is continued as long as the clinical effect of Afinitor is maintained and there are no signs of intolerable toxicity.
For the treatment of patients with SEGA, the initial dose of Afinitor is 4.5 mg / m2 of body surface, rounded to the nearest existing drug dosage. Tablets of different dosages can be combined to obtain the desired dose.
Approximately 2 weeks after starting treatment with SEGA or after any change in liver function, the concentration of everolimus in the blood should be assessed. To achieve the optimal therapeutic effect, dose titration may be required, since well tolerated and effective doses are different for each patient.
Every three months after initiation of therapy, it is necessary to assess the volume of the SEGA tumor.
When Afinitor is prescribed for other indications (except for SEGA), the recommended dose is 10 mg once a day.
If severe and / or intolerable side effects develop, you should reduce the dose of Afinitor by 50% or temporarily stop treatment. Patients receiving everolimus at a dose of 2.5 mg per day can be switched to taking the drug every other day.
When administered together with moderate P-glycoprotein inhibitors or CYP3A4 inhibitors, the dose of Afinitor should be reduced to 5 mg per day. If at the same time severe and / or intolerable side effects develop, the drug is taken 5 mg per day every other day.
When administered together with strong inducers of P-glycoprotein or inducers of the CYP3A4 isoenzyme, the dose of everolimus can be gradually increased from 10 to 20 mg per day (the dose increment is 5 mg).
In case of impaired renal function and in patients 65 years of age and older, dose adjustment is not required.
In case of liver dysfunction, the dose is adjusted as follows:
- SEGA in patients over 18 years of age with mild liver dysfunctions - 75% of the standard dose, calculated by body surface area;
- SEGA in patients over 18 years of age with moderate hepatic dysfunction - 25% of the standard dose, calculated by body surface area;
- SEGA in patients over 18 years of age with severe liver dysfunction - Afinitor is contraindicated;
- other indications (except for SEGA) for mild liver dysfunction - 7.5 mg per day;
- other indications (except for SEGA) for moderate liver dysfunction - 2.5 mg per day;
- other indications (except for SEGA) in severe liver dysfunction - Afinitor is contraindicated.
Side effects
- digestive system: very often - stomatitis, taste changes, anorexia, vomiting, nausea, diarrhea; often - dyspepsia, dysphagia, abdominal pain, dry mouth;
- cardiovascular system: often - increased blood pressure; sometimes - congestive heart failure;
- nervous system and sensory organs: very often - headache; often - sleep disorders (insomnia), eyelid edema, conjunctivitis; sometimes - loss of taste;
- respiratory system: very often - pneumonitis, shortness of breath, cough, nosebleeds; often - hemoptysis;
- hematopoietic system: very often - anemia, neutropenia, lymphocytopenia, thrombocytopenia;
- endocrine system: often - exacerbation of diabetes mellitus; sometimes - diabetes mellitus, diagnosed for the first time;
- urinary system: often - increased urination during the daytime;
- skin and subcutaneous tissue: very often - dry skin, itching and rash; often - erythema, palmar-plantar syndrome;
- metabolism: very often - an increase in the concentration of glucose, cholesterol, creatinine, triglycerides, a decrease in the concentration of phosphorus in the blood, an increase in the activity of liver enzymes; often - an increase in the level of bilirubin in the blood;
- general reactions: very often - asthenia, accession of secondary infections, increased fatigue, peripheral edema; often - chest pain, dehydration; sometimes - weight loss, fever, slow wound healing.
During treatment with Afinitor, isolated cases of the following adverse reactions were also noted: bleeding of various localization of the first degree of severity, hypersensitivity, manifested by flushing of the face, shortness of breath, chest pain, angioedema or anaphylactic reactions.
In clinical studies, cases of exacerbation of viral hepatitis B (including fatal) and the development of hyperglycemia have been noted.
Overdose
Cases of drug overdose have not been recorded. With a single oral administration of Afinitor in a dose of up to 70 mg, the tolerance was satisfactory.
In case of an overdose of Afinitor, the patient should be monitored and appropriate symptomatic therapy should be provided.
special instructions
Treatment with Afinitor is carried out under the supervision of a specialist who has experience in working with antineoplastic agents.
It is recommended to use reliable contraceptive methods during treatment and for at least two months after stopping everolimus.
Before starting therapy and periodically during the use of Afinitor, it is necessary to monitor renal function, glucose levels and drug concentration in the blood, conduct a clinical blood test, monitor the content of blood cells and the concentration of triglycerides and cholesterol.
If symptoms of non-infectious pneumonitis appear, it may be necessary to reduce the dose of everolimus or to completely cancel the Afinitor.
During treatment with Afinitor, the risk of developing viral, bacterial, protozoal and fungal infections increases, so if signs of any disease appear, you should inform your doctor about this, who will prescribe the appropriate treatment.
In case of invasive systemic fungal infection, it is necessary to discontinue Afinitor and apply appropriate antifungal therapy.
In case of stomatitis, inflammation and ulceration of the oral mucosa, local treatment is recommended, however, hydrogen peroxide, thyme derivatives, iodine and alcohol-containing products should not be used for rinsing the mouth, as their use may worsen the patient's condition.
When prescribing Afinitor, children and adolescents under 18 years of age should first be vaccinated with antiviral vaccines according to the local immunization schedule.
During treatment, care is required when driving a car and engaging in other potentially hazardous activities (work of a dispatcher, operator, etc.).
Application during pregnancy and lactation
Afinitor is contraindicated for use during pregnancy and breastfeeding. During therapy with Afinitor and for at least 2 months after its completion, it is recommended to use reliable methods of contraception.
Pediatric use
Afinitor is not recommended for the treatment of patients under the age of 1 year. In the treatment of children with subependymal giant cell astrocytomas, doses similar to those in adult patients are recommended (excluding cases of liver dysfunction).
In case of impaired liver function of classes A, B, C according to the Child-Pugh classification, Afinitor is contraindicated in patients under the age of 18 for the treatment of subependymal giant cell astrocytomas associated with tuberous sclerosis.
With impaired renal function
In case of impaired renal function, dose adjustment is not required.
For violations of liver function
The drug is contraindicated for the treatment of patients with subependymal giant cell astrocytomas with severe liver dysfunction (class C according to the Child-Pugh classification). In severe hepatic impairment, the drug is not recommended for use (except in cases where the potential risk is lower than the intended benefit).
For mild and moderate impairment of liver function (classes A and B according to the Child-Pugh classification), dose adjustment is required.
In case of liver dysfunctions of classes A, B, C according to the Child-Pugh classification, it is forbidden to use Afinitor in the treatment of subependymal giant cell astrocytomas associated with tuberous sclerosis in patients under the age of 18 years.
Use in the elderly
When treating elderly patients, dose adjustment is not required.
Drug interactions
P-glycoprotein inhibitors can increase the serum concentration of everolimus. Afinitor can increase plasma concentrations of drugs metabolized with the participation of CYP3A4 and CYP2D6 inhibitors.
The bioavailability of everolimus increases when taken simultaneously with erythromycin, verapamil and cyclosporine.
The concentration of everolimus in the blood may increase with simultaneous use with the following drugs: macrolide antibiotics (erythromycin, etc.), antifungal agents (fluconazole), protease inhibitors (indinavir, nelfinavir, amprenavir), calcium channel blockers (diltiazem, nicardipine), verapamil.
The concentration of everolimus in the blood may decrease when used simultaneously with the following drugs: rifampicin, anticonvulsants (phenobarbital, carbamazepine, phenytoin), St. John's wort, drugs for the treatment of HIV (nevirapine, efavirenz).
When used together with glucocorticosteroids or other immunosuppressive drugs, the likelihood of developing pneumocystis pneumonia increases; with ACE inhibitors - the risk of developing angioedema increases.
During treatment with Afinitor, it is recommended to avoid the use of grapefruit juice and grapefruit.
Immunosuppressants can influence the response to vaccination, so it may be less effective during everolimus treatment. It is recommended to avoid the use of live vaccines.
Analogs
The analogues of the Afinitor are: Gleevec, Votrien, Certikan, Nexavar, Everolimus.
Terms and conditions of storage
Store in a dry, dark place at a temperature not exceeding 30 ° C. Keep out of the reach of children.
The shelf life is 3 years.
Terms of dispensing from pharmacies
Dispensed by prescription.
Reviews about Afinitor
Reviews of Afinitor are predominantly positive: it is effective in monotherapy and in the complex treatment of kidney cancer (2nd line drug), renal angiomyolipoma, giant cell astrocytomas, metastatic breast cancer (after a course of therapy with aromatase inhibitors).
Some reviews contain information about side effects: the appearance of hiccups, itchy skin, barley.
Price for Afinitor in pharmacies
The approximate price for Afinitor is: 30 tablets of 2.5 mg - from 58,000 to 99,000 rubles, 30 tablets of 5 mg - from 93,000 to 130,000 rubles, 30 tablets of 10 mg - from 148,000 to 189,000 rub. Dispersible tablets can be purchased at prices ranging from 82,000 to 125,000 rubles. (in a package of 30 tablets of 2 mg).
Affinitor: prices in online pharmacies
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Drug name Price Pharmacy |
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Afinitor 2.5 mg tablets 30 pcs. RUB 88,250 Buy |
Anna Kozlova Medical journalist About the author
Education: Rostov State Medical University, specialty "General Medicine".
Information about the drug is generalized, provided for informational purposes only and does not replace the official instructions. Self-medication is hazardous to health!
