Imatinib-TL - instructions for use, dose, side effects, contraindications

Imatinib has a selective inhibitory effect on the Bg-Abl-tyrosine kinase enzyme formed by the fusion of the Bcr (breakpoint cluster region) and the Abl (Abelson) protooncogene at the cellular level, selectively inhibits proliferation and induces apoptosis of the Bcr-Abl tyrosine kinase expressing cell lines , including immature leukemia cells formed in patients with positive for the Philadelphia chromosome chronic myeloid leukemia and acute lymphoblastic leukemia.

Imatinib selectively inhibit Bcr-Abl-positive colonies obtained from the blood of patients with chronic myeloid leukemia.

Imatinib inhibits proliferation and induces apoptosis of gastrointestinal stromal tumor cells expressing tyrosine kinase with a c-Kit receptor mutation.

Activation of receptors to platelet growth factors or Abl fragment of tyrosine kinase may cause the development of both myelodysplastic / myeloproliferative diseases (MDS / MPZ) and hypereosinophilic syndrome and chronic eosinophilic leukemia and swelling dermatofibrosarcoma. Activation of the c-Kit receptor tyrosine kinase and receptors for platelet growth factors may underlie the pathogenesis of systemic mastocytosis. Imatinib inhibits signaling in cells and cell proliferation resulting from impairment of regulation of activity

factors of platelet and stem cell growth, c-Kit receptor and AAbl-fragment of tyrosine kinase.

Pharmacokinetics:

Suction. After oral administration, the bioavailability of the drug is on average 98%. The coefficient of variation for the indicator area under the concentration-time curve (AUC) is 40-60%. When taking the drug with a high-fat diet, compared with fasting, there is a slight decrease in the degree of absorption (a decrease in the maximum concentration of imatinib in the blood plasma by about 11%, AUC - about 7.4%) and slowing the rate of absorption achieving the maximum concentration of imatinib in the blood plasma for 1.5 h). Distribution. According to the in vitro data, with clinically significant concentrations of imatinib, its binding to blood plasma proteins is about 95% (mainly with albumin and acid alpha-glycoprotein, to a negligible degree - with lipoprotein).

Metabolism. The main metabolite of imatinib circulating in the bloodstream is the N-demethylated piperazine derivative, which in vitro has pharmacological activity similar to that of the unchanged starting material.The area under the pharmacokinetic curve (AUC) for the metabolite is only 16% of the Imatinib AUC. The binding of a metabolite with plasma proteins is similar to that of imatinib.

Excretion. After the administration of 1 C-labeled imatinib within 7 days, 68% of the administered dose and 13% of the dose were excreted by the intestine. In an unchanged form, about 25% of the dose is excreted (20% by the intestine and 5% by the kidneys). The rest of the imatinib is excreted as metabolites.

The half-life period (T1 / 2) of imatinib in healthy volunteers was about 18 hours. In the dose range of 25 to 1000 mg, a direct linear dependence of the AUC value on the dose value was noted. With the use of repeated doses, prescribed once a day, the pharmacokinetics of imatinib did not change. The value of the equilibrium concentration (Css) exceeded the value of the initial concentration by 1.5-2.5 times.

Pharmacokinetics in different groups

In the group of people older than 65 years, an increase in the volume of distribution by 12% was found, which seems clinically insignificant. The influence of body weight on the clearance value of imatinib was noted. For patients with a body weight of 50 kg, the average clearance (C1) of imatinib is 8.5 l / h, and for patients with a body weight of 100 kg, 11.8 l / h.However, these differences do not appear to be so significant that a dose change is required depending on the patient's body weight. The pharmacokinetics of imatinib does not depend on sex. Changes in clearance and volume distribution of imatinib with simultaneous use with other drugs are not significant and do not require dose changes.

As in adult patients, children and adolescents under the age of 18 years have a rapid absorption of the drug when ingested. AUC in the dose range of 260 and 340 mg / m2 is similar to that in adults in the dose range of 400 and 600 mg, respectively. When comparing the values of AUC (O-24) on days 1 and 8, after repeated administration of the drug at a dose of 340 mg / m 2, 1.7 fold cumulation of imatinib is noted once a day.

In patients with varying degrees of impaired liver function, the mean AUC values do not increase.

When imatinib is used in patients with impaired renal function of mild or moderate severity (creatinine clearance> 30 ml / min), an increase in plasma exposure in the plasma is approximately 1.5-2.0 times, corresponding to an increase in the concentration of acid alpha-glycoproteins (major proteins plasma binding to imatinib). Correlations between the exposure of the drug and the severity of renal disorders have not been revealed.

Indications:

- The first identified positive for the Philadelphia chromosome (Ph +) chronic myeloid leukemia (XML) in children and adult patients;

- Ph + XML in the chronic phase with failure of previous therapy with interferon alpha or in the phase of acceleration, or blast crisis in children and adult patients;

- The first diagnosed positive for the Philadelphia chromosome (Ph +) acute lymphoblastic leukemia (OLL) in adult patients in combination with chemotherapy;

- Recurrent or refractory Ph + ORL in adult patients as monotherapy;

- Myelodysplastic / myeloproliferative diseases (MDS / MPD) associated with gene rearrangements of the platelet-derived growth factor receptor in adult patients;

- Systemic mastocytosis (CM) in adult patients with no D816V c-Kit mutation or with an unknown c-Kit mutation status;

- Hypereosinophilic syndrome and / or chronic eosinophilic leukemia (HES / CEL) in adult patients with positive or negative abnormal FIP1L1-PDGFR alpha-tyrosine kinase;

- Inoperable, relapsing and / or metastatic swelling dermatofibrosarcoma in adult patients.

Contraindications:Hypersensitivity to the active substance or any other component of the drug, pregnancy, breastfeeding, children under 2 years of age (safety and efficacy not currently established).

Carefully:It should be used with caution imatinib patients with severe hepatic insufficiency, severe renal dysfunction, cardiovascular disease and / or in the presence of risk factors for heart failure, as well as in the regular hemodialysis procedure.

Pregnancy and lactation:

Currently, there are no data on the use of imatinib in pregnant women. Studies conducted on animals have shown toxic effects on reproductive function, but the potential risk to the fetus is still unknown. Imatinib is contraindicated during pregnancy. Women of childbearing age during therapy with imatinib and at least 3 months after treatment should use effective methods of contraception.

At present, it is not known whether imatinib with breast milk in lactating women.In studies conducted in animals, it was shown that the unchanged drug and / or its metabolites are released in significant quantities with milk. Women receiving imatinib, you should stop breastfeeding.

Dosing and Administration:

Inside, with food, drinking a full glass of water. Doses of 400 and 600 mg / day should be taken in 1 dose; The daily dose of 800 mg should be divided into 2 doses - 400 mg in the morning and in the evening.

Patients who are not able to swallow the whole capsule, for example, children, the drug can be taken in a diluted form; the contents of the capsules are diluted with water or apple juice. The necessary amount of the contents of the capsules is placed in a beaker, filled with liquid (approximately 50 ml of capsule liquid 100 mg) and stirred with a spoon; as a result, a slurry is formed. The resulting suspension should be taken immediately after preparation.

In chronic myeloid leukemia (XML) the recommended dose of imatinib depends on the phase of the disease. In the chronic phase of XML, the dose is 400 mg / day; in the phase of acceleration and with a blast crisis - 600 mg / day. The drug should be taken 1 time / day. Treatment with the drug is carried out as long as the clinical effect remains.In the absence of severe side effects, neutropenia or thrombocytopenia not associated with leukemia, an increase in the dose from 400 to 600 or 800 mg / day in patients in the chronic phase of the disease and from 600 to 800 mg / day in patients in the phase of acceleration and with blast crisis. Such a dose increase may be necessary in the progression of XML (at any stage), in the absence of a satisfactory hematologic response after 3 months of treatment, a cytogenetic response at 12 months of therapy, or loss of a previously hematologic and / or cytogenetic response. In children older than 2 years, the calculation of the dosing regimen is based on the surface area of the body. A dose of 340 mg / m / day is recommended for children with a chronic phase of XMJI and an accelerating phase. The total daily dose in children should not exceed 600 mg. The daily dose of the drug can be taken simultaneously or divided into 2 equal doses - in the morning and in the evening.

With Ph + acute lymphoblastic leukemia (ALL) the recommended dose of the drug is 600 mg / day.

In myelodysplastic / myeloproliferative (MDS / MPD) diseases the recommended dose of imatinib is 400 mg / day.

If signs of disease progression appear, imatinib therapy should be discontinued.

With inoperable, recurrent and / or metastatic swelling dermatofibrosarcoma the recommended dose of the drug is 800 mg / day.

With systemic mastocytosis (CM) in the absence of D816V c-Kit mutation, the recommended dose of imatinib is 400 mg / day. With an unknown mutational status and insufficient effectiveness of previous therapy, the recommended dose is 400 mg / day.

In systemic mastocytosis (CM) caused by abnormal FIP1L1-PDGFR a-tyrosine kinase, resulting from the fusion of the Fip likel and PDGFR genes, the recommended initial dose is 100 mg / day. With insufficient effectiveness and no significant side effects, an increase in the dose to 400 mg / day is possible. With a hypereosinophilic syndrome and / or chronic eosinophilic leukemia (HES / HAL) in adults, the recommended dose is 400 mg / day. In adult patients with HES / HAL due to abnormal FIP1L1-PDGFR a-tyrosine kinase, the recommended initial dose is 100 mg / day. With insufficient effectiveness and no significant side effects, an increase in the dose to 400 mg / day is possible.

Correction of the dosing regimen

Patients with impaired hepatic function

Because the imatinib is metabolized mainly in the liver, in patients with mild, moderate or severe impairment of liver function imatinib should be prescribed in a minimum daily dose of 400 mg. With the development of undesirable toxic effects, the dose of the drug should be reduced. Caution is advised to prescribe the drug to patients with severe hepatic impairment. Patients with impaired renal function

Kidneys do not play a significant role in the excretion of imatinib and its metabolites. In patients with impaired renal function or in patients requiring systematic hemodialysis, imatinib treatment should begin with a minimum effective dose of 400 mg once daily, with caution. With imatinib intolerance, the initial dose of the drug can be reduced, with insufficient effectiveness - increased.

Elderly patients

Older patients do not need to adjust the dosage regimen of the drug. Correction of the dosing regimen with the development of non -hematological side effects of the drug

With the development of any serious non-hematologic side effect associated with taking the drug,The therapy should be discontinued until the situation is resolved. The treatment can then be resumed at a dose that depends on the severity of the observed side effect.

With an increase in the concentration of bilirubin and an increase in the activity of "hepatic" transaminases in the serum 3 and 5 times higher than the upper limit of the norm (VGN), respectively, drug treatment should be temporarily suspended until the concentration of bilirubin decreases to less than 1.5 x VGN and the activity of "liver" transaminase to a value of less than 2.5 x VGN.

Imatinib therapy is resumed with a reduced daily dose: in adults, the dose is reduced from 400 to 300 mg / day or from 600 to 400 mg / day, or from 800 to 600 mg / day; in children from 340 to 260 mg / m2 / day.

Correction of the dosing regimen with the development of serious side effects from the blood and lymphatic system (severe thrombocytopenia, neutropenia)

When neutropenia and thrombocytopenia occur It is necessary to temporarily cancel the drug or reduce its dose, depending on the severity of these undesirable phenomena. In CM and HES / HAL, due to an abnormal FIP1L1-PDGFR a-tyrosine kinase (initial dose of imatinib is 100 mg), in the case of a decrease in the absolute number of neutrophils <1 * 109 / L and / or platelet count <50 * 109 / L,

- abolish imatinib until the absolute number of neutrophils is> 1.5 * 109 / l and the number of platelets> 75 * 109 / L;

- resume treatment with imatinib at a dose used before the interruption of therapy.

In the chronic phase of CML in children and adult patients, (Initial dose for adult patients - 400 mg, for children - 340 mg / m2) in the case of a decrease in the absolute number of neutrophils <1 * 109 / L and / or the number of platelets <50 * / MDS / MPZ, CM and HES / 109 / l is recommended:

- abolish imatinib until the absolute number of neutrophils is> 1.5 * 109 / L and the number of platelets> 75 * 109 / L;

- resume treatment with imatinib at a dose used before the interruption of therapy.

In case of a repeated decrease in the number of neutrophils <1 * 109 / l and / or platelet count <50 * 10 / L, you should cancel again imatinib until the absolute number of neutrophils is> 1.5 * 10% and the number of platelets> 75 * 109 / L, and then resume treatment with imatinib in a reduced dose of 300 mg (in children - 260 mg / m).

In the phase of acceleration and overbearing of CML in children and adults and in Ph + acute lymphoblastic leukemia in adult patients (the initial dose for adults is -600 mg, for children-340 mg / m2) in the case of a decrease in the absolute number of neutrophils <0.5 * 109 / l and / or the amount of platelets <1 * 109 / l after one or more months of treatment is recommended:

- check whether the cytopenia is a consequence of leukemia (bone marrow examination);

- if cytopenia is not associated with leukemia, reduce the dose of imatinib to 400 mg (for children - 260 mg / m2);

- if the dystopia persists for 2 weeks, reduce the dose to 300 mg (for children - 200 mg / m);

- If cytopenia persists for 4 weeks and its association with leukemia is not confirmed, cancel imatinib until the absolute number of neutrophils is> 1 * 109 / l and the number of platelets> 20 * 109 / l; then resume treatment with imatinib at a dose of 300 mg (in children - 260 mg / m2).

With inoperable, recurrent and / or metastatic swelling dermatofibrosarcoma (initial dose of imatinib 800 mg) in the case of a decrease in the absolute number of neutrophils <1 * 109 / L and / or platelet count <50 * 109 / L is recommended:

- abolish imatinib until the absolute number of neutrophils is> 1.5 * 109 / l and the number of platelets> 75 * 10 / L;

- to resume treatment with imatinib at a dose of 600 mg.

In case of a repeated decrease in the number of neutrophils <1 * 109 / l and / or platelet count <50 * 10 / L, you should cancel again imatinib until the absolute number of neutrophils is> 1.5 * 109 / l and the platelet count> 75 * 109 / L, and then resume treatment with imatinib in a reduced dose of 400 mg.

Side effects:

At the advanced stage of malignant diseases, evaluation of adverse events (AEs) of the drug is difficult due to symptoms associated with multiple concomitant disorders, their progression and the intake of various medications. With prolonged daily intake of adults and children with XML imatinib in general, is well tolerated. Most AEs were mild or moderate. Side effects were similar in almost all patients who received imatinib for various indications. The most frequent AEs associated with taking the drug were neutropenia, thrombocytopenia, anemia, headache, dyspepsia, swelling, weight gain, nausea, vomiting, diarrhea, myalgia, muscle cramps, rash, weakness, abdominal pain. All these phenomena were easily stopped.

In the clinical studies of imatinib, the following adverse events were noted, listed below for organs and systems, indicating the frequency of their occurrence: very often (> 1/10), often (> 1/100 to <1/10) infrequently (> 1/1000 to <1/100), rarely (from> 1/10000 to <1/1000), very rarely (<1/10000), including individual messages:

Infectious diseases: infrequent - herpes simplex, herpes zoster, nasopharyngitis, pneumonia, sinusitis, inflammation of the subcutaneous tissue, upper respiratory tract infections, influenza, urinary tract infections, gastroenteritis, sepsis; rarely - mycoses.

Benign, malignant and unspecified neoplasms (including cysts and polyps): rarely - tumor lysis syndrome.

Violations from the blood and lymphatic system: very often - neutropenia, thrombocytopenia, anemia; often - pancytopenia, febrile neutropenia, infrequently - thrombocythemia, lymphopenia, oppression of bone marrow hematopoiesis, eosinophilia, lymphadenopathy; rarely - hemolytic anemia.

Disorders from the metabolism and nutrition: often - anorexia; infrequently - hypokalemia, increase or decrease in appetite, hypophosphatemia, dehydration, hyperuricemia, gout, hypercalcemia, hyperglycemia; hyponatremia; rarely - hyperkalemia, hypomagnesemia.

Disorders from the psyche: often - insomnia; infrequently - depression, anxiety, decreased libido; rarely confusion.

Impaired nervous system: very often - headache; often - dizziness, paresthesia, impaired taste,hypoesthesia; infrequently - migraine, drowsiness, fainting, peripheral neuropathy, memory impairment, sciatica, restless leg syndrome, tremor, hemorrhagic stroke, cerebral edema; rarely - increased intracranial pressure, convulsions, optic neuritis.

Disorders from the side of the organ of vision: often - edema of the eyelids, increased tearing, conjunctival hemorrhages, conjunctivitis, dry eye syndrome, blurred vision; infrequent - eye irritation, eye pain, orbital edema, bleeding in the sclera of the eye, retinal hemorrhage, blepharitis, macular edema, rarely - cataract, edema of the optic nerve, glaucoma, vitreous hemorrhage.

Hearing disorders and labyrinthine disturbances: infrequently - vertigo, tinnitus, hearing loss

Disorders from the cardiovascular system: infrequent - palpitation, chronic heart failure, pulmonary edema, tachycardia, "hot flashes", hemorrhages, thrombosis / embolism; rarely - arrhythmias, atrial fibrillation, sudden cardiac arrest; myocardial infarction, angina, pericardial effusion, increase and decrease of arterial pressure, hematomas,subdural hematomas, cold extremities, Reynaud's syndrome, pericarditis; cardiac tamponade; very rarely - anaphylactic shock.

Disturbances from the respiratory system, chest and mediastinal organs: often - nosebleeds, dyspnea, cough; infrequently - pleural effusion, pain in the pharynx or larynx, pharyngitis, acute respiratory failure, interstitial pneumonia; rarely - pleural pain, pulmonary fibrosis, pulmonary hypertension, pulmonary hemorrhage.

Disorders from the digestive system: very often - nausea, vomiting, diarrhea, indigestion, abdominal pain; often - bloating, flatulence, constipation, gastroesophageal reflux, dry mouth, gastritis; infrequently - stomatitis, ulceration of the oral mucosa, gastrointestinal bleeding, belching, melena, esophagitis, ascites, gastric ulcer, vomiting of blood, cheilitis, dysphagia, pancreatitis, gastrointestinal tumor bleeding / gastrointestinal tumor necrosis, gastrointestinal perforation; rarely - colitis, paralytic / obturation intestinal obstruction, inflammation of the intestine, diverticulitis.

Disorders from the liver and bile ducts: often - increased activity of "liver" enzymes, infrequently - jaundice, hepatitis, hyperbilirubinemia, rarely - liver failure, liver necrosis.

Dermatological reactions: very often - periorbital edema, dermatitis, eczema, skin rash; often - puffiness of the face, itching, erythema, dry skin, alopecia, night sweats, photosensitivity reactions; infrequent - pustular rash, bruises, increased sweating, urticaria, ecchymosis, increased predisposition to hematoma formation, hypotrichosis, hyperpigmentation / hypopigmentation of the skin, exfoliative dermatitis, nail damage, folliculitis, petechiae, psoriasis, purpura, bullous rash; rarely acute febrile neutrophilic dermatosis (Sweet syndrome), nail color change, angioedema, erythema multiforme, leukoclastic vasculitis, Stevens-Johnson syndrome, acute generalized pustular exanthema, palmar-plantar erythrodysesthesia, lichenoid keratosis, lichen planus, toxic epidermal necrolysis.

Disturbances from the osteomuscular and connective tissue: very often - muscle spasms and cramps, musculoskeletal pain, including myalgia, arthralgia,pain in the bones; often swelling of the joints; infrequently - stiffness of muscles and joints; rarely - muscle weakness, arthritis; frequency unknown - growth retardation in children, avascular necrosis / necrosis of the femoral head, rhabdomyolysis / myopathy.

Impaired kidney and urinary system: infrequently - kidney pain, hematuria, acute renal failure, frequent urination.

Disorders from the endocrine system, genital organs and mammary glands: infrequently - gynecomastia, erectile dysfunction, menorrhagia, menstrual irregularities, sexual dysfunction, pain in the nipples, enlargement of the mammary glands, swelling of the scrotum; very rarely - bleeding from the cyst of the yellow body / ovary.

Other: very often - fluid retention and swelling, increased fatigue, weight gain; often - weakness, fever, anasarca, chills, trembling, weight loss; infrequently - chest pain, general malaise, increased creatinine and alkaline phosphatase, creatine phosphokinase, lactate dehydrogenase in the blood serum; rarely - increased activity of amylase in the blood plasma.

Overdose:

There are reports of individual cases of imatinib overdose.

Overdose in adults

In one case, imatinib in a dose of 1200-1600 mg for 1-10 days in patients were observed: nausea, vomiting, diarrhea, rash, erythema, swelling, swelling of the face, increased fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain , headache, decreased appetite.

When taking the drug at a dose of 1800-3200 mg, weakness, myalgia, an increase in the activity of creatine phosphokinase activity, bilirubin concentration, and gastrointestinal pain were noted.

When the drug was administered at a dose of 6400 mg once (information from the published source), the patient developed nausea, vomiting, abdominal pain, hyperthermia, edema of the face, decreased platelet count and increased activity of "liver" transaminases. When taking the drug at a dose of 8-10 g, vomiting and gastrointestinal pain were noted once.

Overdose in children and adolescents

When taking the drug at a dose of 400 mg once in children at the age of 3 years, there were vomiting, anorexia, diarrhea, and at a dose of 980 mg - a decrease in the number of white blood cells and diarrhea. Treatment: medical supervision and symptomatic therapy are recommended. The antidote of imatinib is not known.

Interaction:

With the simultaneous use of imatinib with drugs that inhibit the cytochrome P450 isoenzyme CYP3A4 (ketoconazole, itraconazole, erythromycin, clarithromycin), possibly slowing the metabolism of imatinib and increasing its concentration in the blood plasma. Caution is necessary when combined with imatinib with inhibitor preparations of CYP3A4 isoenzymes.

In contrast, the simultaneous use of drugs that are inducers of the isoenzyme CYP3A4 (for example, rifampicin, dexamethasone, preparations from St. John's wort, peritoneal, antiepileptic drugs: carbamazepine, oxcarbazepine, phenytoin, phenobarbital, fosphenytoin, primidon) can lead to an acceleration of the metabolism of imatinib and, consequently, concentration in the blood plasma. With the simultaneous use of imatinib and simvastatin, there was an increase in the maximum drug concentration (Stach) and AUC of simvastatin by 2 and 3.5 times, respectively, which is a consequence of the inhibition of the isoenzyme CYP3A4 by imatinib. It is advisable to use caution when using imatinib and preparations that are substrates of the CYP3A4 isoenzyme and have a narrow range of therapeutic concentrations (for example, ciclosporin and pimozide). Imatinib can increase serum concentrations of other drugs metabolized by the isoenzyme CYP3A4 (triazolo-benzodiazepines, dihydropyridine, slow calcium channel blockers, most HMG-CoA reductase inhibitors, including statins).

Imatinib also inhibits the isoenzyme CYP2C9 and the isoenzyme CYP2C19 in vitro. Elongation of prothrombin time was observed with the combined use of imatinib with warfarin. With simultaneous application with coumarin derivatives, short-term prothrombin time monitoring at the beginning and end of therapy with the drug, as well as a change in the dosage regimen of imatinib, is necessary. As an alternative to warfarin, consideration should be given to the use of low molecular weight heparins.

When a combination of imatinib with chemotherapeutic drugs in high doses, it is possible to develop transient hepatic toxicity in the form of an increase in the activity of "hepatic" transaminases and hyperbilirubinemia.

With a combination of imatinib and regimens of chemotherapy that can potentially cause liver dysfunction, liver function should be monitored.

In vitro imatinib inhibits the cytochrome P450 isoenzyme CYP2D6 at the same concentrations in which it inhibits the CYP3A4 isoenzyme.

When imatinib is used together with metoprolol, the substrate of the isoenzyme CYP2D6, there is a moderate decrease in metoprolol metabolism, accompanied by an increase in Stach and AUC. Given the moderate increase in the effects of drugs that are substrates of the isoenzyme CYP2D6 (eg, metoprolol), when combined with imatinib, there is no need to change the dosage regimen. In vitro imatinib inhibits O-glucuronidation of paracetamol / acetaminophen. Caution should be exercised when prescribing imatinib together with paracetamol / acetaminophen because of the possible development in patients with acute hepatic insufficiency with a fatal outcome.

Special instructions:

Treatment with imatinib should be done only under the supervision of a doctor who has experience with antitumor drugs.

When handling the drug, avoid contact with the skin and eyes, as well as inhaling the powder of the drug.

Experience with imatinib treatment in children with CML younger than 2 years is limited, the experience of using the drug for other indications is limited in patients under 18 years of age.It is recommended to carry out a careful growth control in children using imatinib, in connection with the available reports of a delay in their growth.

When using imatinib, regular clinical studies of peripheral blood are recommended and liver function control (transaminase, bilirubin, alkaline phosphatase) should be performed.

Care should be taken to monitor patients with heart and kidney disease.

Due to the fact that when imatinib is applied in 1-2% of cases, there is a marked fluid retention, it is recommended to regularly monitor the body weight of patients. In the case of a sudden, sudden increase in body weight, a patient should be examined and, if necessary, temporarily discontinued imatinib therapy and / or diuretics. The highest frequency of fluid retention is observed in elderly patients with concomitant cardiovascular diseases. In some cases, severe fluid retention may have a severe course with a fatal outcome. When administering the drug, patients with liver disease should regularly perform a clinical blood test and determine the activity of "liver" enzymes.Since there are reports of the development of hypothyroidism with imatinib in patients who undergone thyroidectomy and who are receiving levothyroxine replacement therapy, it is necessary to regularly determine the level of thyroid-stimulating hormone in this category of patients.

In patients with hypereosinophilia syndrome and heart disease, individual cases of cardiogenic shock / left ventricular failure were noted at the beginning of imatinib therapy. These undesirable phenomena stop after the introduction of systemic glucocorticosteroids, the adoption of measures aimed at maintaining blood circulation, and the temporary withdrawal of imatinib.

In patients with MDS / MPD and high levels of eosinophils, ECG testing should be performed and the serum concentration of cardiospecific troponin should be determined. When detecting abnormality of the start of therapy should be considered a prophylactic use of systemic glucocorticoids (1-2 mg / kg) for 1-2 weeks, concurrently with imatinib.

In patients with malignant gastrointestinal stromal tumors, gastrointestinal bleeding and hemorrhage of metastatic foci were noted.Bleeding was observed both in the organs of the abdominal cavity and in the liver, depending on the localization of tumor sites.

Women of childbearing age during therapy with imatinib and, at least within 3 months after, should use reliable methods of contraception.

Effect on the ability to drive transp. cf. and fur:Some side effects of the drug, such as dizziness and blurred vision, can adversely affect the ability to drive and perform potentially hazardous activities. In the event of the above symptoms, one should refrain from driving vehicles and practicing other potentially dangerous activities that require an increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:Capsules 50 mg and 100 mg.

Packaging:

For 10 or 12 capsules in a planar cell packaging made of polyvinylchloride film and aluminum foil printed lacquered.

For 60 or 100 or 120 capsules in a polymer canister for medicines.

Each bank, 6 or 10 or 12 contiguous cell packs, along with the

application put in a pack of cardboard box.

Storage conditions:In the dark place at a temperature of no higher than 25 ° C. Keep out of the reach of children.

Shelf life:

2 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002478

Date of registration:26.05.2014

The owner of the registration certificate:TECHNOLOGY OF DRUGS, LTD. TECHNOLOGY OF DRUGS, LTD. Russia

Manufacturer: & nbsp

TECHNOLOGY OF DRUGS, LTD. Russia

Information update date: & nbsp26.05.2014

Illustrated instructions

Instructions

Imatinib-TL (Imatinib-TL)