Afinitor

Treatment should only be performed by physicians experienced in immunosuppressive therapy after organ transplantation and the ability to monitor everolimus whole blood concentrations.

Patients with basal concentrations of 3 ng/mL or more have a lower incidence of acute rejection (renal and cardiac) than patients with basal concentrations less than 3 ng/mL.

The recommended upper limit for the therapeutic concentration of everolimus is 8 ng/ml.

In patients with liver failure, while using strong CYP3A4 inducers and inhibitors, when switching to another drug and/or if the dose of cyclosporine is significantly reduced, it is necessary to monitor the concentration of everolimus in the blood.

Everolimus concentrations with dispersible tablets are slightly lower than with conventional tablets.

Since cyclosporine interacts with everolimus, a decrease in the concentration of the latter is possible if the concentration of cyclosporine is significantly reduced (basal concentration less than 50 ng/ml).

Everolimus should not be used long-term with full dose cyclosporine. A reduction in the dose of cyclosporine begins 1 month after renal transplantation, which leads to an improvement in renal function.

Recommended concentration of cyclosporine (2 hours after administration): 0-4 weeks - 1000-1400 ng/ml; 5-8 weeks - 700-900 ng/ml; 9-12 weeks - 550-650 ng/ml; 13-52 weeks - 350-450 ng/ml. In this case, the basal concentration of cyclosporine should be (ng/ml): 1st month - 125-353; 3rd month - 46-216; 6th month - 22-142; 12th month - 33-89.

It is very important (in the early period after transplantation) that everolimus and cyclosporine concentrations are not reduced below the therapeutic range in order to minimize the risk of failure. Before reducing the dose of cyclosporine, it should be clarified that the steady-state concentration of everolimus is 3 ng/ml or more.

There are limited data on the use of everolimus when basal cyclosporine concentrations are less than 50 ng/mL or maintenance cyclosporine concentrations are less than 350 ng/mL.

If the patient does not tolerate a dose reduction of cyclosporine, subsequent use of everolimus should be reconsidered.

In patients after heart transplantation, the dose of cyclosporine should be reduced in the maintenance phase to improve renal function.

If renal function deteriorates or if CC is less than 60 ml/min, adjustment of the therapy regimen is necessary. The dose of cyclosporine is determined based on its basal concentration.

In cardiac transplantation, there are limited data on the use of everolimus when basal cyclosporine concentrations are less than 175 ng/ml in the first 3 months; less than 135 ng/ml - in the 6th month; less than 100 ng/ml - after 6 months.

Everolimus is used simultaneously with cyclosporine in the form of a microemulsion, basiliximab and GCS.

Concomitant use with potent CYP3A4 inhibitors (ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir) and inducers (rifampicin, rifabutin) is not recommended, unless the expected benefit of therapy outweighs the potential risk.

Everolimus blood concentrations should be monitored when used concomitantly with CYP3A4 inducers or inhibitors and after their discontinuation.

During treatment, patients should be monitored to identify skin neoplasms; It is necessary to minimize exposure to UV radiation, sunlight, and use appropriate sunscreens. The risk of skin neoplasms is related to the duration and intensity of immunosuppression rather than to the use of a specific drug.

Excessive immunosuppression predisposes to the development of infections, especially opportunistic ones. There are reports of fatal infections and sepsis.

For 3 months after transplantation, it is recommended to prevent CMV infection (in patients with an increased risk of developing infection).

Concomitant use of everolimus with cyclosporine (microemulsion) increases serum cholesterol and TG levels, which may require appropriate treatment. Patients should be monitored to identify hyperlipidemia, if necessary, treated with lipid-lowering drugs and prescribed an appropriate diet.

If hyperlipidemia is detected when prescribing immunosuppressive drugs, it is necessary to assess the risk/benefit ratio.

The risk/benefit ratio of continuing everolimus therapy in patients with severe refractory hyperlipidemia should be assessed. Patients receiving HMG-CoA reductase inhibitors and/or fibrates should be monitored for the development of adverse events caused by the above drugs.

During treatment, all patients are recommended to monitor renal function. If CC increases, the issue of adjusting immunosuppressive therapy (reducing the dose of cyclosporine) should be addressed.

Caution should be exercised when simultaneous use of other drugs that have a negative effect on renal function. There are limited data on the use of everolimus in pediatric renal transplant recipients.

In patients with hepatic impairment, basal whole blood concentrations of everolimus should be carefully monitored.

Women of childbearing potential should be advised to use effective methods of contraception during treatment and for 8 weeks after the end of therapy.

Afinitor®

Suction

The maximum concentration (Cmax) of everolimus in the blood after taking the drug orally in doses of 5 to 70 mg (on an empty stomach or with a small amount of low-fat food) is achieved after 1-2 hours. Cmax when taking the drug daily varies in proportion to the dose in the range from 5 to 10 mg. When taking a single dose of everolimus 20 mg or higher, the increase in Cmax occurs less than proportionally to the dose, however, the value of the area under the curve “dosage and administration method”).

Patients with impaired renal function

A significant effect of creatinine clearance (from 25 to 178 ml/min) on the clearance (CL/F) of everolimus was not detected in patients with progressive solid tumors. Post-transplant renal dysfunction (creatinine clearance from 11 to 107 ml/min) did not affect the pharmacokinetics of everolimus in patients after organ transplantation.

Patients aged ≤18 years

The use of everolimus in children and adolescents under 18 years of age according to the following indications: advanced and/or metastatic renal cell cancer and advanced and/or metastatic neuroendocrine tumors of the gastrointestinal tract, lung and pancreas, hormone-dependent advanced breast cancer, renal angiomyolipoma associated with tuberous sclerosis in the absence of SEGA is contraindicated.

Patients aged ≥ 65 years

There was no significant effect of patient age (from 27 to 85 years) on the clearance of everolimus (CL/F from 4.8 to 54.7 l/h) after oral administration.

Impact of race

Everolimus clearance (CL/F) after oral administration does not differ between Caucasians and Mongoloids with similar liver function.

According to a population pharmacokinetic analysis, in blacks after organ transplantation, the clearance of everolimus (CL/F) (after oral administration) was on average 20% greater than in Caucasians.

Effect of Exposure on Efficiency

There was some correlation between the decrease in 4E-BP1 phosphorylation in tumor tissue and the Cmin of everolimus in the blood at steady state after daily administration of 5 or 10 mg of the drug.

Additional evidence suggests that the reduction in S6 kinase phosphorylation is highly sensitive to mTOR inhibition by everolimus. Suppression of phosphorylation of the translation initiation factor eIF-4G was complete at all values of everolimus Cmin determined in the blood when taking the drug daily at a dose of 10 mg.

Afinitor®

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

When using the drug, the most common adverse reactions (frequency ≥10%) were (in descending order of frequency): stomatitis, skin rash, diarrhea, fatigue, infections, asthenia, nausea, peripheral edema, loss of appetite, headache, pneumonitis, change taste perception, nosebleeds, inflammation of the mucous membranes, vomiting, itching, cough, shortness of breath, dry skin, nail damage and increased body temperature. The most common grade 3-4 adverse reactions (incidence ≥2%) were: stomatitis, fatigue, diarrhea, infections, pneumonitis and diabetes mellitus.

Determination of the frequency of adverse reactions that occurred when taking the drug Afinitor® at a dose of 10 mg/day: very often (≥1/10), often (≥1/100 and <1/10), infrequently (≥1/1000 and <1/10). 100), rare (≥1/10,000 and <1/1000), very rare (<1/10,000), including isolated reports.

Infectious and parasitic diseases:

very often - infections (opportunistic infections, exacerbation of viral hepatitis B).

Metabolism and nutrition:

very often - loss of appetite, loss of body weight; often - dehydration.

From the endocrine system:

often - exacerbation of existing diabetes mellitus; infrequently - newly diagnosed diabetes mellitus.

From the cardiovascular system:

often - bleeding, increased blood pressure; uncommon - deep vein thrombosis, chronic heart failure.

From the nervous system:

very often - changes in taste perception, headache, dizziness; infrequently - loss of taste sensitivity.

From the mental side:

often - insomnia.

From the side of the organ of vision:

often - conjunctivitis, swelling of the eyelids.

From the respiratory system:

very often - cough, pneumonitis (including alveolitis, interstitial lung disease, alveolar pulmonary hemorrhage, pulmonary infiltration, pulmonary toxicity), epistaxis, shortness of breath; often - pulmonary embolism, hemoptysis; infrequently - acute respiratory distress syndrome.

From the digestive system:

very often - stomatitis (including aphthous stomatitis and ulceration of the tongue and oral mucosa), diarrhea, nausea, vomiting; often - dry mouth, pain in the oral cavity, abdominal pain, dyspepsia, dysphagia.

From the musculoskeletal system:

often - arthralgia.

From the urinary system:

often - proteinuria, renal failure, frequent urination during the day.

For the skin and subcutaneous tissues:

very often - rash, dry skin, itching, damage to the nail plates; often - acne, palmoplantar erythrodysesthesia syndrome, erythema.

From the hematopoietic system:

infrequently - true erythrocyte aplasia of the bone marrow.

General violations:

very often - increased fatigue, asthenia, inflammation of the mucous membranes, peripheral edema, increased body temperature, decreased body weight; often - chest pain; infrequently - slow wound healing.

Allergic reactions:

When using everolimus, there have been cases of hypersensitivity, manifested by anaphylactic reactions, shortness of breath, flushing, chest pain or angioedema (for example, swelling of the airways and tongue with or without breathing problems).

From the laboratory parameters:

≥ 10% (in descending order) - decreased hemoglobin, lymphopenia, leukopenia, neutropenia, thrombocytopenia; increased concentrations of cholesterol, triglycerides, glucose, increased AST activity, increased creatinine, increased ALT activity, increased serum bilirubin, hypophosphatemia and hypokalemia. Most laboratory abnormalities were mild to moderate. Severe (grade 4) abnormalities included lymphopenia (2.2%), decreased hemoglobin (2%), hypokalemia (2%), neutropenia (<1%), thrombocytopenia (<1%), hypophosphatemia (<1%), and increased creatinine (1%), cholesterol (<1%), AST activity (<1%), ALT (<1%), bilirubin (<1%), glucose (<1%) in serum.

Subependymal giant cell astrocytomas

Clinical trial data (average duration of therapy - 9.6 months)

Most common (≥ 10%):

stomatitis.

Grade 3 adverse reactions (≥ 2%)

were represented by stomatitis, neutropenia, and viral gastroenteritis. No grade 4 adverse reactions were recorded.

Determination of the frequency of adverse reactions when using the drug Afinitor®: very often (≥1/10), often (≥1/100 and <1/10), infrequently (≥ 1/1000 and <1/100), rarely (≥ 1/10) 10,000 and <1/1000), very rare (<1/10,000), including isolated reports.

Infectious and parasitic diseases:

upper respiratory tract infections, otitis media, pneumonia; often - viral gastroenteritis.

From the respiratory system:

often - cough, nosebleeds, pneumonitis.

From the hematopoietic system: often - neutropenia, anemia.

From the digestive system:

very often - stomatitis (includes ulceration of the oral mucosa, lips); often - pain in the mouth, gastritis, vomiting.

For the skin and subcutaneous tissues:

often - rash (includes maculopapular rash, macular rash, generalized rash).

From the nervous system:

often - convulsions.

Mental disorders:

often - aggressiveness, insomnia.

Common disorders:

often - fatigue, irritability, increased body temperature, gait disturbances.

From the reproductive system:

often - amenorrhea, irregular menstrual cycle.

Laboratory and instrumental data:

often - increased concentration of triglycerides in the blood, increased concentration of total cholesterol in the blood plasma, increased LDL levels.

Deviations in laboratory and instrumental parameters observed with a frequency of ≥10% (in descending order): hematological -

increased aPTT, decreased absolute neutrophil count, anemia;
biochemical -
hypercholesterolemia, increased AST activity, hypertriglyceridemia, increased ALT activity, hypophosphatemia, hypokalemia.

Most of the above adverse reactions were mild (1) or moderate (2) in severity.

There were cases of decrease in the absolute number of neutrophils of grade 3 severity.

Data from a phase 2 clinical trial (average treatment duration: 34 months).

The adverse reactions described below were observed only in phase 2 clinical studies.

Infectious and parasitic diseases:

very often - sinusitis, inflammation of the subcutaneous tissue, gastroenteritis, pharyngitis, inflammation of the external ear, skin infections, herpes zoster, stomach infections, urinary tract infections, nasopharyngitis; often - abscess of the extremities, viral bronchitis.

For the skin and subcutaneous tissues:

very often - acneiform dermatitis, acne, furunculosis.

From the digestive system:

very often - diarrhea, often - vomiting, gastritis.

From the side of the organ of vision:

very often - conjunctivitis.

From the urinary system:

often - proteinuria.

Laboratory and instrumental data:

often - a decrease in the concentration of immunoglobulin G in the blood.

Deviations in laboratory and instrumental parameters observed with a frequency of ≥ 10%: hematological -

leukopenia, thrombocytopenia, lymphopenia;
biochemical -
increased alkaline phosphatase activity, increased glucose and creatinine concentrations, decreased glucose concentrations. There were cases of increased AST activity, grade 3 alkaline phosphatase and a decrease in the absolute number of neutrophils and lymphocytes of grade 4 severity.

Renal angiomyolipoma not requiring immediate surgical intervention in patients with tuberous sclerosis

Most common (frequency ≥1/10%):

stomatitis, hypercholesterolemia, acne, fatigue, anemia, increased LDH activity in the blood plasma, leukopenia and nausea.
The most common adverse reactions of grade 3-4 (frequency ≥ 2%):
stomatitis, amenorrhea. One death was reported in a patient receiving Afinitor®; death was a consequence of status epilepticus. There was no association between the cause of death and the use of Afinitor®.

Infectious and parasitic diseases: often -

urinary tract infections, sinusitis, upper respiratory tract infections.

From the hematopoietic system:

very often - anemia, leukopenia, often - thrombocytopenia.

From the side of metabolism:

often - loss of appetite.

From the nervous system:

often - headache, changes in taste perception, loss of taste sensitivity.

From the respiratory system:

often - cough, pneumonitis, nosebleeds.

From the digestive system:

very often - stomatitis (including aphthous stomatitis and ulceration of the tongue and oral mucosa), nausea; often - diarrhea, vomiting, abdominal pain, flatulence.

For the skin and subcutaneous tissues:

very often - acne, often - acneiform dermatitis, dry skin, papules.

From the reproductive system:

often - amenorrhea, irregular menstrual cycle, uterine bleeding, vaginal bleeding, opsomenorrhea.

General violations:

very often - increased fatigue.

From the immune system:

often - hypersensitivity reactions.

From the urinary system:

often - acute renal failure.

From the laboratory parameters:

very often - increased LDH activity; often - hypophosphatemia, hyperlipidemia, iron deficiency; ≥10% (in descending order) - decreased hemoglobin in the blood serum, leukopenia, neutropenia, thrombocytopenia, hypercholesterolemia, hypertriglyceridemia, increased activity of AST, ALT, increased concentrations of glucose, bilirubin in the blood, decreased phosphorus levels in the blood serum. Most of the above adverse reactions were mild (grade 1) or moderate (grade 2). The most common laboratory abnormalities of grade 3-4 are hypophosphatemia (5.1%), hypofibrinogenemia (2.5%), lymphopenia (1.3%) and neutropenia (1.3%), increased alkaline phosphatase activity (1.3%), AST (1.3%), ALT (1.3%), hyperkalemia (1.3%).

Adverse reactions of particular clinical interest

In clinical studies, when using the drug, there were cases of exacerbation of viral hepatitis B, including cases with a fatal outcome. Worsening infections are expected during periods of immunosuppression.

When using everolimus, according to clinical studies and spontaneous reports during post-marketing observation, cases of renal failure (including death) and proteinuria were observed.

It is recommended to monitor renal function.

When using everolimus, according to clinical studies and spontaneous reports registered in the post-registration period, cases of amenorrhea (including secondary amenorrhea) were observed.