No cases of drug overdose have been reported.
Treatment: in case of an overdose of Afinitor® it is necessary to monitor the patient, as well as prescribe appropriate symptomatic therapy. With a single oral administration of the drug in doses up to 70 mg, its tolerability was satisfactory.
hypersensitivity to everolimus, other rapamycin derivatives, or any of the auxiliary components of the drug,
severe hepatic impairment (Child-Pugh class C) (lack of data on efficacy and safety),
pregnancy and breast-feeding,
children and adolescents under 18 years of age (no data on efficacy and tolerability).
The simultaneous use of everolimus with strong inducers of the CYP3A4 isoenzyme or inducers of P-glycoprotein (P-GP pump) should be avoided.
With caution: Caution should be exercised when using everolimus concomitantly with moderate CYP3A4 inhibitors or P-GP inhibitors.
Afinitor® It should not be used in patients with rare hereditary disorders associated with galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption.
Since when using rapamycin derivatives, including Afinitor®, the healing process of wounds may slow down, caution should be exercised when prescribing the drug to patients before surgical interventions.
Everolimus is a substrate of CYP3A4, as well as a substrate and a moderately active inhibitor of P-glycoprotein (P-GP pump), which provides the release of many drug compounds from cells. Therefore, the absorption and subsequent excretion of everolimus may be affected by substances that interact with CYP3A4 and/or P-GP.
In vitro everolimus exhibits the properties of a competitive CYP3A4 inhibitor and a mixed CYP2D6 inhibitor.
Drugs that can increase the concentration of everolimus in the blood
The concentration of everolimus in the blood may increase when used together with drugs that are inhibitors of the CYP3A4 isoenzyme (reducing the metabolism of everolimus) or P-GP pump (reduction of everolimus release from intestinal cells). Concomitant use of everolimus with strong CYP3A4 or P-GP inhibitors (including ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, clarithromycin, nefazodone, ritonavir, atazanavir, saquinavir, darunavir, indinavir, nelfinavir and other drugs with similar activity) should be avoided.
The systemic bioavailability of everolimus increased significantly (increase in Cmax and the AUC of the drug, respectively, by 4.1 and 15.3 times) in healthy subjects when everolimus was co-administered with ketoconazole, which is a strong inhibitor of CYP3A4 and P-GP.
Caution should be exercised when co-administration of everolimus with moderate CYP3A4 inhibitors (including erythromycin, verapamil, cyclosporine, fluconazole, diltiazem, amprenavir, fosamprenavir, or aprepitant) or P-GP. When used together with moderate CYP3A4 or P-GP inhibitors, the dose of Afinitor® it should be reduced.
The systemic bioavailability of the drug in healthy subjects increased with simultaneous use with:
- erythromycin (moderately active inhibitor of CYP3A4 and P-GP, Cmax and the AUC of everolimus increased by 2 and 4.4 times, respectively),
- verapamil (moderately active inhibitor of CYP3A4 and P-GP, Cmax and the AUC of everolimus increased by 2.3 and 3.5 times, respectively),
- cyclosporine (CYP3A4 substrate and moderate P-GP inhibitor, Cmax and the AUC of everolimus increased by 1.8 and 2.7 times, respectively).
Other moderate inhibitors of CYP3A4 and P-GP that may increase the concentration of everolimus in the blood include some antifungal agents (e.g., fluconazole) and some BCCs (e.g., diltiazem).
Drugs that can reduce the concentration of everolimus in the blood
The concentration of everolimus in the blood may decrease when used together with drugs that are inducers of the CYP3A4 isoenzyme (increased metabolism of everolimus) or the P-GP pump (increased release of everolimus from intestinal cells). The simultaneous use of everolimus with strong CYP3A4 inducers or P-GP inducers should be avoided. If you need to use an Afinitor® together with strong inducers of CYP3A4 or inducers of P-GP (for example, rifampicin or rifabutin), the dose of the drug should be increased.
In healthy volunteers who received previous therapy with rifampicin (600 mg/day for 8 days), with subsequent use 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 reduce the concentration of everolimus in the blood (for example, St. John's wort, corticosteroids: for example, dexamethasone, prednisone, prednisone, some anticonvulsants: carbamazepine, phenobarbital, phenytoin, drugs for the treatment of HIV: efavirenz, nevirapine).
The effect of everolimus on the plasma concentration of drugs used as concomitant therapy
In healthy volunteers, the concomitant use of everolimus with atorvastatin (a CYP3A4 substrate) or pravastatin (not a CYP3A4 substrate) showed no clinically significant pharmacokinetic interaction. The effect of simvastatin (a CYP3A4 substrate) on the clearance of everolimus was also not revealed in the population pharmacokinetic analysis.
In vitro everolimus competitively inhibited the metabolism of the CYP3A4 — cyclosporine substrate and was a mixed inhibitor of the CYP2D6 — dextromethorphan substrate. Average Stationary Cmax everolimus when taking the compound orally at a dose of 10 mg per day or 70 mg per week is more than 12-36 times lower than the K valuesi compounds by inhibitory action in vitro on CYP3A4 and CYP2D6. Therefore, the influence of everolimus in vivo the metabolism of the CYP3A4 and CYP2D6 substrates is unlikely.
Other types of interactions that can affect the concentration
Simultaneous use of Afinitor should be avoided® with grapefruits, grapefruit juice and other products that affect the activity of cytochrome P450 and P-GP.
Vaccination
Immunosuppressants may affect the response during vaccination, against the background of treatment with Afinitor® vaccination may be less effective. The use of live vaccines should be avoided.
When using the drug, the most common adverse events (frequency ≥10%) were stomatitis, skin rash, fatigue, asthenia, diarrhea, anorexia, nausea, inflammation of the mucous membranes, vomiting, cough, peripheral edema, infections, dry skin, nosebleeds, itching and shortness of breath. The most common adverse events (AES) of 3-4 degrees of severity (frequency ≥2%) were: infections, stomatitis, increased fatigue and pneumonitis.
When using the drug, the frequency of refusal of therapy due to the development of NYA was 6%. In clinical studies, most of the NSAIDs that developed as a result of the use of the drug and placebo had the 1st or 2nd degree of severity.
AES of the 3rd or 4th degree of severity were observed in 39% of patients taking Afinitor®.
Below are the NES that occurred when using the Afinitor® (10 mg per day), indicating 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), including individual reports.
From the side of the hematopoietic organs: very often — lymphocytopenia, anemia, thrombocytopenia, neutropenia.
From the nervous system: very often — headache, often-insomnia, sometimes-loss of taste sensitivity.
On the part of the visual organ: often-conjunctivitis, edema of the eyelids.
From the CCC side: often-arterial hypertension, sometimes-congestive heart failure.
From the respiratory system: very often — cough, pneumonitis, nosebleeds, shortness of breath, often — hemoptysis.
From the digestive system: very often-anorexia, stomatitis, diarrhea, nausea, vomiting, taste changes, 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%).
From the endocrine system: often-exacerbation of existing diabetes mellitus, sometimes-first-time diabetes mellitus.
Metabolic disorders: very often — increasing the concentration of cholesterol, triglycerides, glucose, creatinine, increased activity of AST, ALT, reducing the concentration of phosphorus in the blood, often increasing the concentration of bilirubin in the blood.
Other: very often-increased fatigue, asthenia, peripheral edema, the addition of secondary infections, often-dehydration, chest pain, sometimes-slow wound healing, fever, weight loss.
There were also isolated cases of bleeding of various localization of the 1st degree of severity.
When using everolimus, there have been cases of hypersensitivity, manifested by anaphylactic reactions, shortness of breath, flushes of blood to the face, chest pain or angioedema (for example, edema of the respiratory tract and tongue without or with respiratory disorders).
In clinical studies with the use of the drug, the development of hyperglycemia was noted.
In clinical studies, when using the drug, cases of exacerbation of viral hepatitis B, including death, were noted. Exacerbation of infections is expected during periods of immunosuppression.
According to the recipe.
Treatment with Afinitor® it should be carried out only under the supervision of a doctor who has experience with antitumor drugs.
During Afinitor therapy® and at least for 2 months after that, you should use reliable methods of contraception.
Before starting 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 should be performed.
Non-infectious pneumonitis is a class-specific side effect of rapamycin derivatives. When using the Afinitor® Cases of non-infectious pneumonitis (including interstitial lung disease) have also been reported.). In some cases, severe forms of the disease were observed (rarely fatal). The diagnosis of non-infectious pneumonitis should be assumed in patients in the development of such nonspecific manifestations on the part of the respiratory system, as hypoxia, pleural effusion, cough, or shortness of breath, and when you exclude using appropriate diagnostic studies of infectious, neoplastic, and other causes of these symptoms. Patients should inform the attending physician about the appearance of any new or increased existing respiratory symptoms. Patients who have only radiological signs of non-infectious pneumonitis (in the absence of clinically significant symptoms) can continue treatment with Afinitor® without changing the dose of the drug. If the symptoms of pneumonitis are moderate, it is necessary to consider temporarily suspending therapy until the symptoms disappear. For relief of symptoms, corticosteroids 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® it should be stopped. 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® It has immunosuppressive properties and can contribute to the development of bacterial, fungal, viral or protozoal infections in patients, especially those caused by opportunistic microorganisms. In patients who took Afinitor® local and systemic infections, including pneumonia, other bacterial infections, as well as fungal infections such as aspergillosis or candidiasis, and viral infections, including exacerbation of viral hepatitis B. Some of these infections were severe (with the development of respiratory or liver failure) and sometimes fatal. Patients should be informed about the increased risk of developing infections when using Afinitor®, be attentive to the symptoms and signs of infections and, if they appear, consult a doctor in a timely manner.
Patients with fungal infections prior to assignment of Afinitor® proper treatment should be provided.
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 mouthwashes containing alcohol or hydrogen peroxide should be avoided, since their use can worsen the condition. Antifungal agents should only be used if a fungal infection is confirmed.
Before starting treatment with Afinitor® and periodically during therapy with the drug, you should monitor the content of glucose in the blood serum on an empty stomach. Before starting treatment with Afinitor® it is necessary to ensure optimal control of blood glucose levels.
Influence on the ability to drive vehicles and work with mechanisms
Study of the effect of Afinitor® the ability to drive and work with mechanisms was not tested.
Advanced and / or metastatic renal cell carcinoma with ineffective antiangiogenic therapy.
Active substance of the drug Afinitor® — everolimus is an inhibitor of the transmission of proliferative signals.
Everolimus is a selective inhibitor of serine-threonine kinase mTOR (the target of rapamycin in mammals), specifically affecting the complex of mTORC1 signal-converting mTOR kinase and regulatory associated protein of mTOR). The mTORC1 complex is the most 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 exhibits its activity due to its high affinity interaction with the intracellular receptor protein FKBP12. The FKBP12–everolimus complex binds to mTORC1, inhibiting its ability to transmit signals
The signaling function of mTORC1 is realized by modulating the phosphorylation of distal effectors, of which the translation regulators are most fully characterized: ribosomal protein kinase S6 (S6K1) and eukaryotic cell elongation factor-4E-binding protein (4E-BP). Impaired function of S6K1 and 4E-BP1 due to inhibition of mTORC1 disrupts the translation of encoded mRNA of the main proteins involved in the regulation of the cell cycle, glycolysis, and adaptation of cells to low oxygen levels (hypoxia). This suppresses tumor growth and the expression of hypoxia-induced factors (e.g., HIF-1 transcription factor). The latter leads to a decrease in the expression of factors that enhance the processes of angiogenesis in the tumor (for example, vascular endothelial growth factor-SEFR)
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 that progressed after previous therapy with tyrosine kinase inhibitors and/or cytokines, everolimus significantly reduced the risk of disease progression and death by 67%. When using the drug, the survival rate of patients without disease progression was 4.9 months. Within 6 months, 36% of patients treated with everolimus did not show any progression of the disease. The use of everolimus can significantly improve the quality of life of patients (the impact of the symptoms of the disease on various areas of the patient's life was evaluated)
Suction
Cmax everolimus in the blood after ingestion of the drug in doses from 5 to 70 mg (on an empty stomach or with a small amount of low-fat food) is reached in 1-2 h. Cmax when taking from 5 to 10 mg of the drug daily or weekly, it changes proportionally to the dose. When taking everolimus at doses of 20 mg per week and above, an increase in Cmax it occurs less than proportionally to the dose, but the AUC values increase proportionally to the dose when taking from 5 mg to 70 mg of the drug. When taking everolimus at a dose of 10 mg, food with a high fat content reduced the AUC and Cmax of the drug, respectively, by 22 and 54%. Food with low fat content reduced the AUC and Cmax by 32% and 42%, respectively. However, food intake did not have a significant effect on the elimination rates of the drug.
Distribution
The percentage of everolimus amounts in the blood and blood plasma, which is dependent on the concentration of the compound in the range from 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 concentrations of the substance recorded in the blood of cancer patients taking everolimus 10 mg per day. Binding to plasma proteins is approximately 74% in both healthy subjects and patients with moderately impaired liver function.
In experimental studies, it was shown that after intravenous administration, the penetration of everolimus through the BBB depends on the dose non-linearly, which implies saturation of the BBB pump, which ensures the drug's entry from the blood into the brain tissue. The penetration of everolimus through the BBB was also demonstrated in animals that received the drug orally.
Metabolism
Everolimus is a substrate of CYP3A4 and P-glycoprotein (P-GP). After oral administration of the drug, everolimus circulates in the blood mostly unchanged. In human blood, six major metabolites of everolimus were identified, represented by three monohydroxylated metabolites, two open-ring hydrolytic conversion products, and the phosphatidylcholine conjugate of everolimus. These metabolites were about 100 times less active than everolimus. Therefore, it is generally assumed that most of the total pharmacological activity of everolimus is due to the action of an unchanged compound.
Excretion
After administration of a single dose of radiolabeled everolimus to patients, most (80%) of the radioactivity was detected in the feces, a small amount (5%) was excreted in the urine. The unchanged substance was not detected either in the urine or in the feces.
Pharmacokinetics in the equilibrium state
After a daily or weekly intake of everolimus, the AUC values are0–t they were proportional to the dose of the drug when it was used in doses from 5 to 10 mg per day and from 5 to 70 mg per week. The steady-state (equilibrium) state was achieved within two weeks with a daily intake of everolimus. Cmax everolimus was proportional to the dose when using the drug in doses of 5 to 10 mg per day or per week. At doses of 20 mg per week and above, the increase in Cmax it was less than proportional to the dose. Tmax the blood plasma was 1-2 hours. When everolimus was taken daily, there was a significant correlation between the AUC value after reaching the equilibrium state0–t and the concentration of the drug in the blood before taking the next dose. T1/2 everolimus is about 30 hours.
Pharmacokinetics in selected groups of patients
Patients with impaired liver function. The average AUC in patients with moderate hepatic impairment (Child-Pugh class B) was twice as high as in patients with normal hepatic function. There was a positive correlation between the AUC value on the one hand and the concentration of bilirubin in the blood serum and the lengthening of the PV on the other. A negative correlation was found between the AUC values and the serum albumin concentration. The effect of severe hepatic impairment (Child-Pugh class C) 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. Posttransplatational renal impairment (creatinine clearance from 11 to 107 ml / min) did not affect the pharmacokinetics of everolimus in patients after organ transplantation.
Patients aged less than 18 years. The use of the drug in children and adolescents with tumors under the age of 18 years has not been previously studied.
Patients aged ≥65 years. There was no significant effect 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 oral administration of the drug.
The influence of race. The clearance of everolimus (CL/F) after oral administration of the drug in persons of the Caucasian and Mongoloid races, cancer patients with similar liver function does not differ.
According to the population pharmacokinetic analysis, the clearance of everolimus (CL/F) after oral administration was on average 20% higher in Negroid individuals after organ transplantation than in Caucasian individuals.
The effect of exposure on efficiency. There was some correlation between the decrease in phosphorylation of 4E-BP1 in the tumor tissue and the average Cmin everolimus in the blood in a stationary (equilibrium) state after daily administration of 5 or 10 mg of the drug. Additional evidence suggests that the decrease in phosphorylation of S6 kinase is very sensitive to mTOR inhibition under the influence of everolimus. Suppression of phosphorylation of the translation initiation factor elF-4G was complete at all values of Cmin everolimus, determined in the blood with a daily intake of the drug at a dose of 10 mg.
At a temperature not exceeding 30 °C, in the original packaging.
Keep out of reach of children.
Shelf life of the drug Afinitor®3 года.Do not use after the expiration date indicated on the package.
| Pills | 1 table. |
| active substance: | |
| everolimus (stabilized with 0.2% butylhydroxytoluene) | 5 mg |
| 10 mg | |
| excipients: 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 a blister pack of 10 pcs., in a pack of cardboard 3, 6 and 9 blisters.
Inside. Afinitor® It should be taken 1 time a day daily 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 can not be chewed or crushed.
Treatment with the drug is carried out as long as the clinical effect persists.
Recommended dose of Afinitor® it is 10 mg once a day. With the development of severe and/or difficult-to-tolerate adverse events, the dose of Afinitor should be reduced® up to 5 mg/day and / or temporarily discontinue therapy with the drug.
When used simultaneously with moderate inhibitors of CYP3A4 and P-GP, the dose of Afinitor® it should be reduced to 5 mg/day. With the development of severe and / or difficult-to-tolerate adverse events in patients receiving the drug simultaneously with moderate inhibitors of CYP3A4 and P-GP, the dose of Afinitor® it is necessary to reduce 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 gradually by the doctor's decision from 10 mg / day to 20 mg/day (the value of a step-by-step increase in the dose is 5 mg).
It is assumed that the appointment of Afinitor® at a dose of 20 mg 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). Upon discontinuation of therapy with strong inducers of CYP3A4 or P-GP Afinitor® it should be administered at the dose in which the patient took it before starting treatment with strong inducers of CYP3A4 or P-GP.
Patients aged ≥65 years: no dose adjustment is required.
Patients with impaired renal function: no dose adjustment is required.
Patients with impaired liver function: in patients with moderate hepatic impairment (class B according to the Child-Pugh classification), the dose of Afinitor® it should be reduced to 5 mg per day.
L01XE10 Everolimus
