Description of the drug AFINITOR
Immunosuppressant, inhibitor of proliferative signal transmission. The immunosuppressive effect is due to the inhibition of antigen-activated T cell proliferation and, accordingly, clonal expansion caused by specific T cell interleukins, for example, interleukin-2 and interleukin-15. Everolimus inhibits the intracellular signaling pathway that normally leads to cell proliferation triggered by the binding of these T cell growth factors to their corresponding receptors. Blockade of this signal by everolimus stops cell division at the G1 stage of the cell cycle.
At the molecular level, everolimus forms a complex with the cytoplasmic protein FKBP-12. In the presence of everolimus, growth factor-stimulated p70 S6 kinase phosphorylation is inhibited. Because p70 S6 kinase phosphorylation is under the control of FRAP (called m-TOR), these data suggest that the everolimus-PKBP-12 complex binds to FRAP. FRAP is a key regulatory protein that controls cellular metabolism, growth and proliferation; disruption of FRAP function thus explains the cell cycle arrest induced by everolimus. Everolimus therefore has a different mechanism of action from cyclosporine. In preclinical allotransplantation models, the combination of everolimus and cyclosporine has been shown to be more effective than either alone.
In addition to its effect on T cells, everolimus inhibits growth factor-stimulated proliferation of both hematopoietic and non-hematopoietic cells (eg, smooth muscle cells). Growth factor-stimulated proliferation of vascular smooth muscle cells, which is triggered by damage to endothelial cells and leads to the formation of neointima, plays a key role in the pathogenesis of chronic rejection.
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 prior treatment with tyrosine kinase inhibitors and/or cytokines, everolimus significantly reduced the risk of disease progression and death by 67%. When using everolimus, survival of patients without disease progression was 4.9 months. Within 6 months, 36% of patients receiving everolimus did not experience disease progression. It is believed that the use of everolimus can significantly improve the quality of life of patients (the impact of disease symptoms on various areas of the patient’s life was assessed).
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®.
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: 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.
