Index of drugs

Treatment: children and adolescents with newly diagnosed chronic myeloid leukemia (CML) with Philadelphia chromosome (brc-abl, Ph +), which are not eligible for bone marrow transplantation as first-line treatment; children and adolescents with Ph + CML in the chronic phase when treatment with Interferon alpha is ineffective or in the accelerated phase of the disease; adult patients as well as children and adolescents with Ph + CML in the course of blast crisis; adult patients and children and adolescents with newly diagnosed Philadelphia chromosome (Ph + ALL) acute lymphoblastic leukemia in combination with chemotherapy; adult patients with recurrent or refractory Ph + ALL monotherapy; adult patients with myelodysplastic / myeloproliferative syndromes (MDS / MPD) associated with the rearrangement of the platelet derived growth factor receptor (PDGFR) gene; adult patients with advanced hypereosinophilic syndrome (HES) and / or chronic eosinophilic leukemia (CEL) with FIP1L1-PDGFRα rearrangement. The effects of imatinib have not been evaluated on the result of bone marrow transplantation. In addition, the drug is indicated for the treatment of adult patients with inoperable dermatofibrosarcoma (DFSP) and adult patients with recurrent and / or metastatic DFSP who are not eligible for surgery. In adult patients as well as children and adolescents, the efficacy of imatinib treatment was assessed on the basis of the overall hematology and cytogenetic response rate as well as the disease-free survival period in CML, hematologic and cytogenetic response rate in Ph + ALL, MDS / MPD, hematologic response rate in HES / OBJECTIVE and based on objective response rate in adult patients with inoperable and / or metastatic DFSP. The experience with the use of imatinib in patients with MDS / MPD associated with PDGFR gene rearrangement is very limited. With the exception of newly diagnosed chronic myelogenous leukemia (CML), there are no controlled trials demonstrating clinical benefit or increased survival in these indications.

1 tabl powl. contains 100 mg or 400 mg of imatinib as methanesulfonate; Table. contain orange yellow.

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 +). 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. It is 95% bound to plasma proteins. 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 drug.

During treatment with imatinib, clinical cases of hypothyroidism have been reported in patients after removal of the thyroid gland, which were substituted for levothyroxine; in such patients, the concentration of thyroid-stimulating hormone (TSH) should be closely monitored.Patients with hepatic impairment (mild, moderate or severe) should be monitored closely for peripheral blood and liver enzymes. It should be noted that patients with gastrointestinal stromal tumors (GISTs) may have metastases to the liver that may lead to dysfunction. Liver damage, including liver failure and hepatic necrosis, has been reported with imatinib. In the case of combination therapy with imatinib and chemotherapy in high doses, there has been an increase in the incidence of serious liver adverse reactions. Liver function should be carefully monitored when imatinib is administered concomitantly with chemotherapy regimens that are known to cause liver problems. Approximately 2.5% of patients with newly diagnosed CML who were taking imatinib had significant fluid retention (pleural effusion, edema, pulmonary edema, ascites, superficial edema); it is highly recommended to regularly monitor the patients' weight. In clinical trials, there was an increase in the number of such cases in elderly patients and patients with a history of cardiac disease; caution should be exercised in patients with cardiac dysfunction. Patients with a history of heart disease, risk factors for heart failure or history of heart failure should be closely monitored and all patients with signs and symptoms consistent with heart or kidney failure require medical assessment and treatment. In patients with hypereosinophilic syndrome with latent infiltration of hypereosinophilic syndrome in the myocardium, the occurrence of single cases of cardiogenic shock / left ventricular dysfunction was associated with hypereosinophilic cell hypertranulation prior to the initiation of imatinib treatment. It has been reported that this condition is reversible after administration of steroids with systemic effects, the use of circulatory maintenance agents and temporary discontinuation of imatinib. Because cardiac adverse events have been reported occasionally after exposure to imatinib, a careful assessment of the benefit-risk balance of imatinib treatment in the HES / CEL population should be made prior to treatment. Myelodysplastic / myeloproliferative syndromes with PDGFR gene rearrangement can be associated with high concentrations of eosinophils; before starting treatment, consideration should be given to consulting the cardiologist, performing an echocardiogram and determining the level of troponin in the serum. 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. In the study in patients with inoperable and / or metastatic GIST, both gastrointestinal bleeding and intra-tumor haemorrhage were found. Based on the available data, no predisposing factors (eg, tumor size, tumor location, coagulation disorders) have been identified 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. Due to the possibility of tumor decay syndrome (TLS), it is recommended to correct clinically significant dehydration and treatment to reduce elevated uric acid levels before starting treatment. In patients taking the drug, a full blood test should be performed regularly. Treatment with imatinib in patients with CML may be associated with the onset of neutropenia or thrombocytopenia. However, the appearance of a reduced number of blood cells probably depends on the severity of the disease and is more common in patients in the accelerated phase of the disease or in the blast crisis than in patients in the chronic phase of CML. In such cases, the treatment may be discontinued or the dose reduced. In patients receiving the drug liver function (aminotransferase, bilirubin, alkaline phosphatase) should be evaluated regularly. 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 increased alpha-acid glycoprotein (AGP), imatinib-binding protein, in plasma in these patients. In patients with impaired renal function a minimum starting dose should be used. Patients with severe renal impairment should be treated with caution. In the case of intolerance, the dose can be reduced.There have been reports of delayed growth in adolescents receiving adolescents prior to adolescence. The long-term effects of long-term treatment with imatinib on growth in children are unknown; Close monitoring of growth in children during treatment with imatinib is recommended. There is no experience regarding use in children with CML below 2 years and in children with Ph + ALL below the age of 1 year. The experience of use in children with MDS / MPD, DFSP and HES / CEL is very limited. The safety and efficacy of imatinib in children with MDS / MPD, DFSP and HES / CEL under 18 years of age have not been established in clinical trials.

The drug 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). Animal studies have shown reproductive toxicity. Women of childbearing age must be informed about the need to use effective contraception during treatment. 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, H. 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, hyperuricaemia, 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, lunar origin, tinnitus, hearing loss, palpitations, tachycardia, congestive heart failure, pulmonary edema, hypertension, hematoma, hematoma subdural, cold fingers of legs and hands, hypotension, Raynaud's syndrome, pleural effusion, sore throat and larynx, sore throat, stomatitis, mouth ulcer, gastrointestinal haemorrhage, belching, tarry stools, esophagitis, ascites, gastric ulcer, bloody vomiting, inflammation of the lips, dysphagia , pancreatitis, hyperbilirubinemia, hepatitis, jaundice, pustular rash, bruising, severe sweating, urticaria, subcutaneous hemorrhage, increased bruising, low hair, skin discoloration, 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, breast enlargement, swelling of the scrotum, chest pain, malaise, increase in creatinine and creatine phosphokinase, lactate dehydrogenase and alkaline phosphatase in the blood.Rarely: fungal infections, tumor lysis syndrome, hemolytic anemia, hyperkalemia, hypomagnesaemia, confusion, increased intracranial pressure, seizures, optic neuritis, cataracts, glaucoma, congestive disc, arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina thoracic, pericardial effusion, pain associated with pleurisy, pulmonary fibrosis, pulmonary hypertension, pulmonary haemorrhage, colitis, ileus, colitis, liver failure, hepatic necrosis, acute dermatitis with fever and neutrophilia (Sweet's syndrome), discoloration of the nails , angioneurotic edema, 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 blood amylase activity. After marketing, tumor haemorrhage / tumor necrosis, anaphylactic shock, cerebral edema, intravitreal haemorrhage, pericarditis, cardiac tamponade, thrombosis / embolism, acute respiratory failure (deaths were reported in patients with advanced disease, severe infections, significant neutropenia and other serious comorbidities), interstitial lung disease, intestinal obstruction, gastrointestinal perforation, diverticulitis, palm-plantar erythrodysaesthesia, lichenoid hyperplasia, lichen planus, epidermal toxic epidermal necrosis, sterile osteonecrosis / bone head necrosis females, growth retardation in children, necrotic and cholestatic hepatitis, and hepatic insufficiency (including cases with fatal outcome).

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: 600 mg / day in the course of blast crisis (the number of blasts in the blood or bone marrow ≥30% or the presence of out-of-group 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 may be considered for the treatment of blast crisis 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.CML in children: 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 drug can be given as one dose per day or 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. Based on existing data, the efficacy and safety of imatinib 600 mg / day in combination with chemotherapy during induction, consolidation and maintenance therapy in adult patients with newly diagnosed Ph + ALL have been demonstrated. The duration of imatinib treatment may vary depending on the treatment program chosen, but in general longer exposure to imatinib gave better results. For adult patients with relapsed or refractory Ph + ALL, imatinib 600 mg / day is safe, effective and can be given until disease progression.Ph + ALL in children: Dosage should be determined based on body surface area (pc.). A daily dose of 340 mg / m is recommended² pc. (Do not use a total dose greater than 600 mg).MDS / MPD in adults: 400 mg / day. In the only clinical trial performed so far, treatment with imatinib was 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. Dose escalation from 100 mg to 400 mg may be considered in the absence of adverse drug reactions 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, from 600 mg to 400 mg or from 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 treatment 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).MDS / MPD (initial dose 400 mg); HES / CEL (after a dose of 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 in section 1 and then return to the medicine at a dose reduced to 300 mg.CML in the chronic phase in children and adolescents (dose 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.Blast crisis and 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 lack of blood cells is not related to leukemia, the dose should be reduced up to 400 mg; 3. if the blood cell deficiency persists for 2 weeks, the dose should be reduced to 300 mg; 4. if the blood cell deficiency persists for 4 weeks and is still not caused by leukemia, treatment should be discontinueduntil ANC ≥ 1.0 x 10⁹/ l and platelets ≥20 x 10⁹/ l, then, the treatment should be resumed with a dose of 300 mg.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.DFSP (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 in section 1 and then return to 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). The tablets can be divided into two equal doses along the dividing line. 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.