Index of drugs

Treatment of children and adolescents with newly diagnosed chronic myeloid leukemia (CML) with Philadelphia chromosome (bcr-abl, Ph +) who are not eligible for bone marrow transplantation as first-line treatment. Treatment of children and adolescents with Ph + CML in the chronic phase when treatment with alpha Interferon is ineffective or in the accelerated phase of the disease. Treatment of adult patients with Ph + CML in blast crisis. Treatment of adult patients with newly diagnosed Philadelphia chromosome (Ph + ALL) acute lymphoblastic leukemia in combination with chemotherapy. Treatment of adult patients with recurrent or refractory Ph + ALL monotherapy. Treatment of adult patients with myelodysplastic or myeloproliferative syndromes (MDS / MPD) associated with the rearrangement of the platelet derived growth factor receptor (PDGFR) gene. Treatment of adult patients with advanced hypereosinophilic syndrome (HES) and / or chronic eosinophilic leukemia (CEL) with FIP1L1-PDGFRα rearrangement. Treatment of adult patients with inoperable dermatofibrosarcoma (DFSP) and adult patients with recurrent and / or metastatic DFSP who are not eligible for surgery.warning. The effects of imatinib on the outcome of bone marrow transplantation have not been evaluated. In adult patients as well as children and adolescents, the efficacy of imatinib was assessed on the basis of the overall hematology and cytogenetic response rate as well as the progression-free survival period in CML, hematologic and cytogenetic response rate in Ph + ALL, MDS / MPD, hematologic response rate in HES / OBJECTIVE and based on the objective response rate in adult patients with DFSP. The experience with the use of imatinib in patients with MDS / MPD associated with PDGFR gene rearrangement is very limited.

1 tabl powl. contains 100 mg or 400 mg of imatinib as mesilate.

An anti-cancer drug - a protein-tyrosine kinase inhibitor. Imatinib strongly inhibits tyrosine kinase (KT) Bcr-Abl and many tyrosine kinase receptors: Kit, stem cell growth factor receptor (SCF) encoded by c-Kit proto-oncogene, discoidine receptor (DDR1 and DDR2) receptors, colony stimulating receptors (CSF) -1R) and platelet-derived growth factor alpha and beta (PDGFR-alpha and PDGFR-beta) receptors. It can also inhibit cellular processes mediated by these kinase receptors. It selectively inhibits proliferation and induces apoptosis in Bcr-Abl positive cells, as well as in leukemic cells freshly collected from patients with CML (chronic myeloid leukemia) with a positive Philadelphia chromosome (Ph +) and from patients with ALL (Philadelphia chromosome positive) . Imatinib is also an inhibitor of platelet kinase activator (PDGF) tyrosine kinase inhibitor, PDGF-R and inhibits cellular processes activated by PDGF. Significant activation of the PDGF receptor or Abl protein-tyrosine kinases as a result of the combination of different corresponding proteins or significant production of PDGF are included in the pathogenesis of MDS / MPD (myelodysplastic / myeloproliferative syndromes), HES / CEL (hypereosinophilic syndrome / chronic eosinophilic leukemia) and DFSP ( nodular fibrosarcoma). Imatinib inhibits signal transduction and cell proliferation dependent on dysregulated regulation of PDGFR activity and Abl kinase. The mean absolute bioavailability of imatinib is 98%. Following oral administration, there was a high inter-individual variation in the AUC of the medicine in the blood. The drug is 95% bound to plasma proteins, primarily with albumin and acid alpha-glycoprotein, and to a small extent with lipoprotein. The main metabolite of imatinib is the N-demethyl derivative of piperazinein vitro it is characterized by a similar potency as the parent compound. The AUC of the metabolite in the blood is only 16% of the imatinib AUC. CYP3A4 is the major cytochrome P450 enzyme involved in the biotransformation of imatinib. The drug is excreted mainly as metabolites in the faeces, to a small extent in the urine.25% of the dose of imatinib is excreted unchanged (of which 20% in the faeces, 5% in the urine). T_0,5 is about 18 hours.

Hypersensitivity to the components of the preparation.

At the same time, strong inducers of CYP3A4 and imatinib (risk of therapeutic failure) should not be used. Caution should be exercised when imatinib is given with strong CYP3A4 inhibitors, substrates of CYP3A4 with a narrow therapeutic index or coumarin derivatives. During treatment with imatinib, a full blood test should be performed regularly; if you have neutropenia or thrombocytopenia, reduce the dose or discontinue imatinib treatment. Liver function (aminotransferase, bilirubin, alkaline phosphatase) should be evaluated regularly; particularly careful monitoring is indicated in patients with impaired hepatic function (the peripheral blood image should also be monitored in detail) and when imatinib is combined with chemotherapy regimens that are known to cause liver dysfunction. It should be noted that patients with GIST may have liver metastases that may lead to dysfunction. During the use of the drug, cases of hypothyroidism have been reported in patients after removal of the thyroid gland, which were substituted for levothyroxine - in these patients TSH levels should be closely monitored. Due to the risk of fluid retention, patients should be regularly monitored for weight. Unexpected, rapid weight gain should be carefully analyzed and appropriate supportive treatment should be given as necessary. The risk of significant fluid retention is higher in elderly patients and patients with a history of heart disease (including history) - be careful. Patients with heart disease, risk factors for heart failure or history of renal impairment should be carefully monitored. In patients with hypereosinophilic syndrome with latent infiltration of hypereosinophilic syndrome in the myocardium, single cases of cardiogenic shock and left ventricular dysfunction have been associated with hypereosinophil cell syndrome degranulation prior to treatment with imatinib. Due to intermittent cardiac side effects, imatinib should be carefully assessed for the benefit-risk balance of treatment with imatinib in the HES / CEL population before starting treatment. MDS / MPD with PDGFR gene rearrangement can be associated with significant eosinophilia. Therefore, in patients with HES / CEL and patients with MDS / MPD with significant eosinophilia, cardiological consultation, echocardiogram and measurement of troponin in serum should be considered prior to initiation of therapy. If any of the results of these tests turn out to be abnormal, further cardiac observation and prophylactic use of systemic steroids (1-2 mg / kg) should be considered for one or two weeks at the start of treatment, along with the administration of imatinib. Before starting treatment with imatinib, due to the possibility of tumor decay syndrome, it is recommended to correct clinically significant dehydration and to reduce elevated uric acid levels. Patients with non-surgical and / or metastatic GISTs have both gastrointestinal bleeding and intra-tumor haemorrhage. There are no predisposing factors that could identify GIST patients to an increased risk of one of these two types of bleeding. Since increased vascularity and bleeding tendency is a hallmark of the natural clinical picture of GIST, standard procedures and procedures should be used to monitor and treat bleeding in all patients. In patients with impaired renal function, the total effect of imatinib in the body appears to be higher than in patients with normal renal function. This is probably due to the elevated alpha acid concentration of the glycoprotein, the imatinib binding protein, in plasma in these patients. In patients with impaired renal function, the drug should be administered with caution, especially in the case of severe kidney problems; if intolerance, reduce the dose of the drug.The long-term effects of long-term treatment with imatinib on growth in children are not known - close monitoring of growth in children is recommended. There is no experience regarding the use of the drug in children with CML <2 years. There is limited experience with the use of imatinib in children with Ph + ALL. The experience of using the drug in children with MDS / MPD and DFSP is very limited. The safety and efficacy of imatinib in children with HES / CEL has not been established.

Animal studies have shown reproductive toxicity. The preparation should not be used during pregnancy unless it is absolutely necessary (in such cases, the patient must be informed about the potential risk to the fetus). Women of childbearing age must be informed about the need to use effective contraception during treatment with the preparation. Imatinib and its active metabolite can pass into breast milk. Considering the combined concentration of imatinib and metabolite and the maximum daily intake of milk by infants, the total predicted exposure is low (~ 10% of the treatment dose). However, because the effects of exposure to an infant on low doses of imatinib are unknown, women who take imatinib should not breast-feed.

Very common: neutropenia, thrombocytopenia, anemia, headache, nausea, vomiting, diarrhea, indigestion, abdominal pain, periorbital edema, dermatitis, eczema, rash, muscle spasms, musculoskeletal pain (including muscle, joint and bone pain) , fluid retention and swelling, fatigue, weight gain. Common: pancytopenia, febrile neutropenia, anorexia, insomnia, dizziness, paresthesia, taste disturbances, hypoaesthesia, eyelid edema, increased tearing, conjunctival haemorrhage, conjunctivitis, dry eye, blurred vision, facial flushing, bleeding, shortness of breath, nosebleed , cough, flatulence, abdominal distension, gastro-oesophageal reflux, constipation, dry mouth, gastritis, increased liver enzymes, pruritus, facial edema, dry skin, erythema, alopecia, night sweats, photosensitivity reaction, swollen joints, weakness, fever, swelling of subcutaneous tissue, chills, stiff muscles, weight loss. Uncommon: virus infectionherpes simplex, herpes zoster, nasopharyngitis, pneumonia, sinusitis, cellulitis, upper respiratory tract inflammation, influenza, urinary tract inflammation, gastroenteritis, sepsis, thrombocytosis, lymphopenia, bone marrow suppression, eosinophilia, lymphadenopathy, hypokalaemia, increased appetite, hypophosphatemia, decreased appetite, dehydration, gout, hyperuricemia, hypercalcemia, hyperglycemia, hyponatremia, depression, decreased libido, anxiety, migraine, drowsiness, fainting, peripheral neuropathy, impaired memory, sciatica, restless legs syndrome, tremor, cerebral haemorrhage eye irritation, eye pain, orbital edema, scleral haemorrhage, retinal hemorrhage, blepharitis, macular edema, dizziness, tinnitus origin, tinnitus, hearing loss, palpitations, tachycardia, congestive heart failure, pulmonary edema, hypertension, hematoma, subdural hematoma, cold toes and legs hands, hypotension, Raynaud's syndrome, pleural effusion, sore throat and larynx, pharyngitis, stomatitis, mouth ulcer, gastrointestinal haemorrhage, belching, tarry stools, esophagitis, ascites, gastric ulcer, bloody vomiting, cheilitis , dysphagia, pancreatitis, hyperbilirubinemia, hepatitis, jaundice, pustular rash, bruising, severe sweating, urticaria, subcutaneous hemorrhage, increased tendency to bruising, scant hair, discoloration of the skin, exfoliative dermatitis, nail fragility, folliculitis, ecchymosis, psoriasis, purpura, excessive skin pigmentation, blistering rashes, joint and muscle stiffness, kidney pain, hematuria, acute renal failure, frequent urination, gynecomastia, erectile dysfunction, menorrhagia, irregular menstruation, sexual dysfunction, nipple pain, enlargement breasts, swelling mo severe chest pain, malaise, increased creatinine and creatine phosphokinase, lactate dehydrogenase and alkaline phosphatase in the blood.Rarely: fungal infections, tumor decay syndrome, hemolytic anemia, hyperkalemia, hypomagnesaemia, confusion, increased intracranial pressure, seizures, optic neuritis, cataracts, glaucoma, congestive disc, arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina pectoris , pericardial effusion, pain associated with pleurisy, pulmonary fibrosis, pulmonary hypertension, pulmonary haemorrhage, colitis, ileus, inflammation of the large intestine, liver failure, hepatic necrosis, acute dermatitis with fever and neutrophilia (Sweet's syndrome), discolored nails, angioedema, follicular rash, erythema multiforme, leukoclastic vasculitis, Stevens-Johnson syndrome, acute generalized pustular exanthema (AGEP), muscle weakness, arthritis, rhabdomyolysis, myopathy, hemorrhagic yellow body / hemorrhagic ovarian cyst, increased activity of amylase in the blood. After marketing, tumor haemorrhage, tumor necrosis, anaphylactic shock, cerebral edema, vitreous hemorrhage, pericarditis, cardiac tamponade, thrombosis, embolism, acute respiratory failure (deaths were reported in patients with advanced disease, severe infections, significant neutropenia and other serious co-morbidities), interstitial lung disease, intestinal obstruction, gastrointestinal perforation, diverticulitis, palm-plantar erythrodysaesthesia, lichenoid hyperplasia, lichen planus, epidermal toxic epidermal necrosis, sterile osteonecrosis, osteonecrosis femoral growth retardation, necrotic and cholestatic hepatitis, and hepatic failure (including cases of deaths, including the death of a patient after taking a high dose of paracetamol).

Orally. Treatment should be carried out by a doctor who has experience in the treatment of patients with hematologic malignancies and sarcoma.CML in adults: in the course of blast crisis, 600 mg / day (blast crisis is defined as a condition in which the number of blasts in the blood or bone marrow is ≥30% or the presence of extramedullary outbreaks of the disease other than in the liver or spleen). In clinical trials, treatment was continued until the disease progressed. The effect of cessation of treatment after full cytogenetic response has not been studied. In patients who do not have severe side effects and serious neutropenia or thrombocytopenia without leukemia, a dose increase from 600 mg to 800 mg (given in two doses of 400 mg) may be considered in the treatment of blast crisis in the following cases: disease progression (every step); no satisfactory haematological response after at least 3 months of treatment; no cytogenetic response after 12 months of treatment; loss of a previously achieved hematological and / or cytogenetic response.CML in children and adolescents: dosage should be determined based on the body surface area (pc.). A dose of 340 mg / m is recommended for children with chronic CML and advanced CML phases² pc. daily (do not use a total dose greater than 800 mg). The preparation can be given as one dose per day or the daily dose can be divided into two parts - one administered in the morning and the other in the evening. No experience in the treatment of children <2 years. In children who have no serious side effects and serious neutropenia or thrombocytopenia without leukemia, a dose increase of 340 mg / m² pc. up to 570 mg / m² pc. daily (do not use a total dose greater than 800 mg) in the following cases: disease progression (at each stage); no satisfactory haematological response after at least 3 months of treatment; no cytogenetic response after 12 months of treatment; loss of a previously achieved hematological and / or cytogenetic response.Ph + ALL in adults: 600 mg / day in combination with chemotherapy during induction, consolidation and maintenance treatment in patients with newly diagnosed Ph + ALL. The duration of treatment may vary depending on the treatment program chosen, but in general longer exposure to the preparation gave better results. For patients with relapsed or refractory Ph + ALL, monotherapy with 600 mg / day imatinib is safe, effective and can be used until the disease progresses.MDS / MPD in adults: 400 mg / day. Duration of treatment: in the only clinical study conducted so far, treatment continued until progression of the disease. At the time of the analysis, the median duration of treatment was 47 months (24 days - 60 months).HES / CEL in adults: 100 mg / day. An increase in the 100 mg to 400 mg dose may be considered in the absence of side effects if the studies show an inadequate response to treatment. Treatment should be continued for as long as the patient benefits from it.DFSP in adults: 800 mg / day.Dosage adjustment due to side effects. Non-haematological side effects. If serious side effects occur, treatment with imatinib should be discontinued until resolution. Then, depending on the initial severity of the adverse event, appropriate treatment can be resumed. If the bilirubin concentration exceeds the upper limit of normal (ULN) by 3 times or hepatic transaminase levels exceed 5-fold ULN, the drug should be discontinued until the bilirubin concentration <1.5 times the GGN value and transaminases <2.5 -GGN value. Treatment can be continued with reduced daily doses. In adults, the dose should be reduced from 400 mg to 300 mg or 600 mg to 400 mg or 800 mg to 600 mg, and in children with 340 mg / m² pc. up to 260 mg / m² pc. per day.Hematologic side effects - thrombocytopenia, neutropenia. HES / CEL (initial dose 100 mg): ANC <1.0 x 10⁹/ l and / or platelets <50 x 10⁹/ l - 1. discontinue the drug until ANC ≥ 1.5 x 10⁹/ l and platelets ≥75 x 10⁹/ L; 2. restart treatment at the previously used dose (ie before the onset of a serious side effect).HES / CEL (after 400 mg), CML in the chronic phase, MDS / MPD (initial dose 400 mg): ANC <1.0 x 10⁹/ l and / or platelets <50 x 10⁹/ l - 1. discontinue treatment until ANC ≥ 1.5 x 10⁹/ l and platelets ≥75 x 10⁹/ L; 2. restart treatment at the previously used dose (i.e. before the onset of a serious side effect); 3. if the ANC is again decreased <1.0 x 10⁹/ l and / or platelets <50 x 10⁹/ l, repeat the procedure given in point 1, and then return to administration of the drug in a dose reduced to 300 mg.CML in the chronic phase in children and adolescents (after a dose of 340 mg / m² pc.): ANC <1.0 x 10⁹/ l and / or platelets <50 x 10⁹/ l - 1. discontinue treatment until ANC ≥ 1.5 x 10⁹/ l and platelets ≥75 x 10⁹/ L; 2. restart treatment at the previously used dose (i.e. before the onset of a serious side effect); 3. if the ANC is again decreased <1.0 x 10⁹/ l and / or platelets <50 x 10⁹/ l, repeat the procedure given in point 1, and then return to administration of the drug at a dose reduced to 260 mg / m² pc.CML in the acceleration and blast crisis phase in children and adolescents (initial dose of 340 mg / m² pc.)ANC <0.5 x 10⁹/ l and / or platelets <10 x 10⁹/ l - 1. check if blood cell deficiency is caused by leukemia (bone marrow aspiration or biopsy); 2. if the lack of blood cells is not related to leukemia, reduce the dose to 260 mg / m² pc .; 3. if the blood cell deficiency persists for 2 weeks, reduce the dose to 200 mg / m² pc .; 4. if the blood cell deficiency persists for 4 weeks and is still not caused by leukemia, discontinue treatment until ANC ≥ 1 x 10⁹/ l and platelets ≥20 x 10⁹/ l, then resume treatment at a dose of 200 mg / m² pc.CML in acceleration and blast crisis in adults, Ph + ALL (initial dose 600 mg)ANC <0.5 x 10⁹/ l and / or platelets <10 x 10⁹/ l - 1. check if blood cell deficiency is caused by leukemia (bone marrow aspiration or biopsy); 2. if the blood cell deficiency is not related to leukemia, reduce the dose of imatinib up to 400 mg; 3. if the blood cell deficiency persists for 2 weeks, reduce the dose to 300 mg; 4. if the blood cell deficiency persists for 4 weeks and is still not due to leukemia, discontinue treatment until ANC ≥ 1 x 10⁹/ l and platelets ≥ 20 x 10⁹/ l, then resume treatment with a 300 mg dose.DFSP (at a dose of 800 mg): ANC <1.0 x 10⁹/ l and / or platelets <50 x 10⁹/ l - 1. discontinue treatment until ANC ≥ 1.5 x 10⁹/ l and platelets ≥75 x 10⁹/ L; 2. resume treatment at a dose of 600 mg; 3. if the ANC is reduced again <1.0 x 10⁹/ l and / or platelets <50 x 10⁹/ l, repeat the procedure given in point 1, and then return to administration of the drug at a dose reduced to 400 mg.Special groups of patients. Patients with mild, moderate or severe hepatic impairment should receive the minimum recommended dose of 400 mg / day; this dose can be reduced if you are intolerant. Patients with renal impairment or dialysis should receive the minimum recommended dose of 400 mg / day as the starting dose; the dose may be reduced in the case of intolerance; if the dose is tolerated, it can be increased if there is no efficacy. There is no need for special dosing in elderly patients.Way of giving. The tablets should be taken with a large glass of water during a meal. The daily dose of 400 mg and 600 mg should be given once a day, while a daily dose of 800 mg should be given in two divided doses (400 mg in the morning and 400 mg in the evening). For patients who are unable to swallow tablets, you can suspend the tablets in a glass of mineral water or apple juice (in approx. 50 ml - 100 mg table and in approx. 200 ml - 400 mg tablet) mix and drink immediately after complete disintegration of the tablet. The 100 mg and 400 mg tablets can also be divided into equal doses.