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

Auxiliary substances (shell): Film Coating Foam Yellow 03F82597 1,203 mg / 4.81 mg contains: hypromellose HPMC 2910 (E 464) - 62.500%, iron dye oxide yellow (E 172) - 20.00%, macrogol (E 1521) - 6.250%, talc (E553b) - 5.00%, titanium dioxide (E171) - 4.750%, iron dye red oxide (E172) - 1.50%.

Description:

Dosage of 100 mg

Round, flat pills covered with a film shell of brownish-orange color, with a risk and with engraving "H" on one side and "19" on the other side. The figures "1" and "9" are divided by risk. On the cross section, the core of the tablet is from white to almost white.

Dosage of 400 mg

The capsule-shaped tablets covered with a film cover of brownish-orange color, with a risk and with engraving "H" on one side and "20" on the other side. The figures "2" and "0" are divided by risk. On the cross section, the core of the tablet is from white to almost white.

Pharmacotherapeutic group:Antitumor agent - protein tyrosine kinase inhibitor

ATX: & nbsp

L.01.X.E.01 Imatinib

Pharmacodynamics:

Imatinib exerts a selective inhibitory effect on the Bcr-A enzymebl-tyrosine kinase, formed by the fusion of a gene site Bcr (breakpoint cluster region) and protooncogene Abl (Abelson), at the cellular level, selectively inhibits proliferation and induces apoptosis of the Bcr-A-expressing cell linesbl-tirozinkinazu, including immature leukemia cells are produced in patients with Philadelphia chromosome positive for chronic myeloid leukemia and acute lymphoblastic leukemia.

Imatinib selectively inhibits Bcr-AbI-positive colonies obtained from blood cells of patients with chronic myelogenous leukemia.

Imatinib inhibits proliferation and induces apoptosis of gastrointestinal stromal tumor cells expressing tyrosine kinase with a mutation c-Kit receptor. Activation of receptors to platelet or platelet growth factorsbl-fragment of tyrosine kinase can cause the development of both myelodysplastic / myeloproliferative diseases, and hypereosinophilic syndrome and chronic eosinophilic leukemia and bulging dermatofibrosarcoma. Activation c-Kit receptor tyrosine kinase and receptors for platelet growth factors can underlie the pathogenesis of systemic mastocytosis. Imatinib inhibits signal transmission in cells and cell proliferation resulting from a disruption in the regulation of platelet-derived growth factors and stem cells, c-Kit- receptor and Abl-fragment of tyrosine kinase.

Pharmacokinetics:

Absorption

After oral administration, the bioavailability of the drug is on average 98%. Coefficient Variations for the indicator area under the "concentration-time" curve (AUC) is a 40-60%.

When taking the drug with food high in fat, in comparison with taking on an empty stomach, 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 - approximately 7.4%) and slowing the rate of absorption (an increase in the time to reach the maximum concentration of imatinib in the blood plasma by 1.5 h).

Distribution

About 95% of imatinib binds to blood plasma proteins (mainly with albumin and acid alpha-glycoproteins, to an insignificant degree - with lipoproteins).

Metabolism

Imatinib is metabolized mainly in the liver with the formation of the main metabolite (N-detylated piperazine derivative) circulating in the blood stream. In vitro the imatinib metabolite has pharmacological activity similar to the activity of the starting material. Value AUC metabolite is about 16% of AUC imatinib. The binding of a metabolite with blood plasma proteins is similar to that of imatinib.

Excretion

After taking one dose, the drug is excreted from the body for 7 days, mainly in the form of metabolites (68% - intestine and 13% - kidney). In an unchanged form, about 25% of the dose is excreted (20% by the intestine and 5% by the kidneys). The half-life of imatinib is about 18 hours.

With repeated administration of the drug once a day, the pharmacokinetic parameters do not change, and the equilibrium concentration of imatinib exceeds the initial concentration by approximately 1.5-2.5 times.

Pharmacokinetics in different groups

Have patients older than 65 years The volume of distribution increases by about 12% that is clinically insignificant. For patients with a body weight of 50 kg, the average clearance of imatinib is approximately 8.5 l / h, and for patients with a body weight of 100 kg, about 11.8 l / h. However, these differences are not significant and do not require correction of the dosage of the drug depending on the patient's body weight.

The pharmacokinetics of imatinib is independent of sex.

Changes in clearance and volume distribution of imatinib with simultaneous use with other drugs are insignificant and do not require dose changes.

As in adult patients, in children and adolescents under 18 years of age there is a rapid absorption of the drug when ingestion.

Patients with varying degrees of impaired liver function mean values AUC do not increase.

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

Indications:

- The newly identified positive for the Philadelphia chromosome (Ph+) chronic myeloid leukemia (CML) in children and adults;

- Ph+ CML in the chronic phase if previous interferon alpha therapy fails or in the accelerated phase, or blast crisis in children and adults;

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

- recurrent or refractory Ph + ALL in adult patients as monotherapy;

- myelodysplastic / myeloproliferative diseases associated with gene rearrangements of the platelet-derived growth factor receptor, in adult patients;

- systemic mastocytosis in adult patients with no D816V from- Kit mutation or with unknown c-Kit mutational status;

- hypereosinophilic syndrome and / or chronic eosinophilic leukemia in adults with positive or negative abnormal FIP1L1-PDGRF alpha-tyrosine kinase;

- Inoperable and / or metastatic malignant gastrointestinal stromal tumors, positive for c-Kit (Cd 117) in adult patients;

- adjuvant therapy of gastrointestinal stromal tumors, positive for c-Kit (Cd 117) in adult patients;

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

Contraindications:

- Hypersensitivity to the active substance or any other component of the drug;

- pregnancy, the period of breastfeeding;

- children under the age of 1 in patients with Ph+ acute lymphoblastic leukemia, up to 2 years in patients with Ph+ chronic myeloid leukemia, up to 18 years for other indications (efficacy and safety not established).

Carefully:

Should carefully assign Imatinib patients with severe hepatic insufficiency, severe impairment of kidney function, cardiovascular disease or in the presence of risk factors for heart failure, as well as regular hemodialysis procedure.

When used simultaneously with preparations inhibiting the isoenzyme CYP3A4, strong isoenzyme inducers CYP3A4, preparations that are substrates of isoenzyme CYP3A4; when used simultaneously with paracetamol, warfarin.

Pregnancy and lactation:

Women of childbearing age during therapy with imatinib should use effective methods of contraception.

Currently, there are no data on the use of imatinib in pregnant women. Imatinib has a toxic effect on reproductive function, but the potential risk to the fetus is still unknown.

Imatinib is contraindicated during pregnancy.

Imatinib and / or its metabolites are excreted in significant amounts with milk, so breastfeeding should be stopped during lactation.

Dosing and Administration:

The drug should be taken with food, washed down with a full glass of water.

Doses of 400 and 600 mg per 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 tablet, for example children, the drug can be taken in a diluted form; pills diluted with water or apple juice. The required amount of tablets or placed in a glass, pour liquid (approximately 100 ml of tablet liquid 400 mg) and stir with a spoon; as a result, a slurry is formed. The resulting suspension should be taken immediately after preparation.

In chronic myelogenous leukemia (CML) recommended dose of the drug Imatinib depends on the phase of the disease. In the chronic phase of CML 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 per day.

Treatment with the drug is carried out as long as the clinical effect remains.

In the absence of severe side effects and neutropenia or thrombocytopenia, no associated with leukemia, it is possible to increase the dose from 400 mg to 600 mg or up to 800 mg in patients in the chronic phase of the disease, and from 600 mg to 800 mg per day in patients in the phase of acceleration and with blast crisis. This increase in dose may be necessary in the progression of CML (any stage), in the absence of a satisfactory hematologic response after 3 months of treatment, cytogenetic response at 12 months of therapy or loss previously achieved hematologic and / or cytogenetic response.

Calculation of dosing regimen in children older than 2 years is based on the surface area of the body. Doses of 340 mg / m² per day are recommended in children with chronic phase of CML and acceleration 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.

When Ph+ acute lymphoblastic leukemia recommended dose of the drug Imatinib is 600 mg per day. Calculation of the dosing regimen in children older than 1 year is based on the surface area of the body. The recommended daily dose is 340 mg / m². The total daily dose in children should not exceed 600 mg. The daily dose of the drug is recommended to be taken simultaneously.

With myelodysplastic / myeloproliferative diseases recommended dose of the drug Imatinib is 400 mg per day.

With inoperable and / or metastatic malignant gastrointestinal stromal tumors recommended dose of the drug Imatinib is 400 mg per day. In the absence of side effects of the drug and an inadequate response, an increase in the daily dose of the drug Imatinib from 400 mg to 600 mg or up to 800 mg.

When there are signs of progression of the disease, drug therapy Imatinib should be discontinued.

When the drug is used as a adjuvant therapy the patients with Gastrointestinal stromal tumors the recommended dose is 400 mg / day. The minimum duration of treatment is 3 years. The optimal duration of adjuvant therapy has not been established.

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

With systemic mastocytosis in the absence of D816V c-Kit mutation, the recommended dose of the drug Imatinib is 400 mg per day. With an unknown mutational status and insufficient effectiveness of previous therapy, the recommended dose is 400 mg per day.

With systemic mastocytosis caused by abnormal FIP1L1-PDGFR a-tyrosine kinase, resulting from the fusion of genes Fip like 1 and PDGFR, the recommended initial dose is 100 mg per 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 (HPP / HAL) in adults, the recommended dose is 400 mg / day. In patients with HES / HAL, caused by abnormal FIP1L1-PDGFR a-tyrosine kinase, the recommended initial dose is 100 mg per day. With insufficient effectiveness and no significant side effects, an increase in the dose to 400 mg / day is possible.

Patients with impaired hepatic function

Because the imatinib is metabolized mainly in the liver, in patients with mild, moderate or severe hepatic impairment 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. Have patients with impaired renal function or in patients requiring systematic hemodialysis, drug treatment Imatinib should begin with a minimum effective dose of 400 mg once a day, taking care when intolerance imatinib 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, therapy should be discontinued until the situation resolves. 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 the activity of liver transaminases in the blood serum 3 and 5 times higher than the upper limit of the norm (VGN), respectively,treatment with the drug should be temporarily suspended until the concentration of bilirubin is reduced to less than 1.5 x VGN and the activity of "hepatic" transaminases to less than 2.5 x VGN.

Drug therapy Imatinib Renew with a reduced daily dose: in adults, the dose is reduced from 400 mg to 300 mg per day or from 600 mg to 400 mg per day, or from 800 mg to 600 mg per day; in children - from 340 to 260 mg /m²per day.

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

In the event of neutropenia and thrombocytopenia, a temporary withdrawal of the drug or a decrease in its dose is required, depending on the severity of these undesirable phenomena.

With systemic mastocytosis (CM) and hypereosinophilic syndrome and / or chronic eosinophilic leukemia (HES / CEL) caused by abnormal FIP1L1-PDGFR a-tyrosine kinase (initial dose of the drug Imatinib 100 mg), in the case of a decrease in the absolute number of neutrophils <1.0 * 10⁹/ l and / or the number of platelets <50 * 10⁹/ l is recommended:

1. abolish Imatinib until the absolute number of neutrophils becomes ≥ 1.5 * 10⁹/ l and platelets ≥75 * 10⁹/ l;

2. resume drug treatment Imatinib in the dose used before the interruption of therapy.

In the chronic phase of CML in children and adults, malignant gastrointestinal stromal tumors, myelodysplastic / myeloproliferative diseases, SM and HES / HAL in adult patients (initial dose for adults - 400 mg, for children - 340 mg / m²) in the case of a decrease in the absolute number of neutrophils <1.0 * 10⁹/ l and / or the number of platelets <50 * 10⁹/ l is recommended:

1. abolish Imatinib until the absolute number of neutrophils becomes ≥1,5*10⁹/ l and platelets ≥75*10⁹/ l;

2. resume drug treatment Imatinib in the dose used before the interruption of therapy.

In the case of a repeated decrease in the number of neutrophils <1.0 * 10⁹/ l and / or the number of platelets <50*10⁹/ l repeat the actions described in paragraph 1, and then resume treatment with the drug Imatinib in a reduced dose of 300 mg (in children - 260 mg / m²).

In the phase of acceleration and power crisis of CML in children and adults and with Ph+ acute lymphoblastic leukemia in adults (initial dose for adults - 600 mg, for children - 340 mg / m²) in the case of a decrease in the absolute number of neutrophils <0.5 * 10 / L and / or the number of platelets <1.0 * 10⁹/ l after one or more months of treatment is recommended:

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

2. if cytopenia is not associated with leukemia, reduce the dose of the drug Imatinib up to 400 mg children 260 mg / m²);

3. if cytopenia persists for 2 weeks, reduce the dose to 300 mg (in children 200 mg / m²);

4. If cytopenia persists for 4 weeks and its association with leukemia is not confirmed, cancel Imatinib until the absolute number of neutrophils is> 1000 / μL and platelets> 20,000 / μL; then resume treatment with the drug Imatinib in a dose of 300 mg (in children - 260 mg / m²).

With inoperable, recurrent and / or metastatic swelling dermatofibrosarcoma (initial dose of the drug Imatinib 800 mg) in the case of a decrease in the absolute number of neutrophils <1.0 * 10⁹/ l and / or the number of platelets <50 * 10⁹/ l is recommended:

1. abolish Imatinib until the absolute number of neutrophils becomes ≥1, 5*10⁹/ l and thrombocytes ≥75 * 107L;

2. resume drug treatment Imatinib in a dose of 600 mg.

In the case of a repeated decrease in the number of neutrophils <1.0 * 10⁹/ l and / or the number of platelets <50 * 10⁹/ l should repeat the actions specified in paragraph 1, and then resume treatment with the drug 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 CML 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. However, in patients with malignant gastrointestinal stromal tumors, myelosuppression was less common; Intra-tumoral bleeding was observed only in this group of patients.

The most frequent AEs associated with taking the drug were neutropenia, thrombocytopenia, anemia, headache pain, dyspepsia, swelling, weight gain, nausea, vomiting, diarrhea, myalgia, muscle cramps, rash, weakness, abdominal pain. All these phenomena were easily stopped.

In clinical trials in patients with CML and with inoperable and / or metastatic malignant gastrointestinal stromal tumors the following undesirable phenomena listed below on bodies and systems with the indication of frequency of their occurrence were noted: very often (≥1 / 10),often (≥1 / 100 <1/10), sometimes (≥ 1/1000 <1/100), rarely (≥1 / 10000 - <1/1000), very rarely (<1/10000), including some messages:

Infectious diseases: sometimes - herpes simplex, herpes zoster, nasopharyngitis, pneumonia, sinusitis, subcutaneous fat inflammation, upper respiratory tract infections, flu, urinary tract infections, gastroenteritis, sepsis; rarely - mycoses.

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

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

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

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

Disturbances from the nervous system: very often - headache; often - dizziness, paresthesia, taste disorder, hypoesthesia; sometimes - migraine, drowsiness, fainting, peripheral neuropathy, memory impairment, sciatica, restless legs syndrome, tremor, hemorrhagic stroke, cerebral edema; rarely - increased intracranial pressure, convulsions, optic neuritis.

Disturbances on the part of the organ of sight: often - eyelid swelling, increased tearing, conjunctival hemorrhage, conjunctivitis, dry eye syndrome, blurred vision; sometimes - eye irritation, eye pain, orbital edema, bleeding in the sclera of the eye, retinal hemorrhage, blepharitis, macular edema; rarely - cataracts, edema of the optic nerve, glaucoma, vitreous hemorrhage.

Hearing disorders and labyrinthine disorders: sometimes - vertigo, noise in the ears, hearing loss.

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

Disturbances from the respiratory system, organs of the chest and mediastinum: often - nosebleeds, dyspnea, cough; sometimes - 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, gastro-esophageal reflux, dry mouth, gastritis; sometimes stomatitis, ulceration of the mucous membrane of the oral cavity, gastrointestinal bleeding, belching, melena, esophagitis, ascites, ulceration of the gastric mucosa, vomiting of blood, cheilitis, dysphagia, pancreatitis, gastrointestinal tumor bleeding / gastrointestinal tumor necrosis, gastrointestinal perforation; rarely - colitis, paralytic / obturation intestinal obstruction, intestinal inflammation, diverticulitis, vascular ectasia of the antral stomach (GAVE-syndrome).

Disturbances from the liver and bile ducts: often - increased activity of "liver" enzymes, sometimes - 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; sometimes - pustular rash, bruises, increased sweating, urticaria, ecchymosis, increased predisposition to the formation of hematomas, 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, red flat lichen; toxic epidermal necrolysis; frequency unknown - drug rash with eosinophilia and systemic symptoms (DRESS).

Disturbances of musculoskeletal and connective tissue: very often - muscle spasms and cramps, musculoskeletal pains, including myalgia, arthralgia, bone pain; often - swelling of the joints; sometimes - 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: sometimes - kidney pain, hematuria, acute renal failure, frequent urination.

Disorders from the endocrine system, genitals and mammary glands: sometimes - 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, tremors, weight loss, sometimes - chest pain, general malaise, increased creatinine and alkaline phosphatase activity, 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. 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 blood of creatine phosphokinase, bilirubin concentration, and gastrointestinal pain were noted.

When using the drug at a dose of 6400 mg once (information from a published source), the patient developed nausea, vomiting, abdominal pain, hyperthermia, facial edema, a decrease in the number of neutrophils and an increase in the activity of "liver" transaminases.

When taking the drug at a dose of 8-10 mg, vomiting and gastrointestinal pain were noted once.

When taking the drug at a dose of 400 mg, once in children aged 3 years, vomiting, anorexia, diarrhea, and a dose of 980 mg - a decrease in the number of leukocytes and diarrhea.

Treatment: recommended medical supervision and symptomatic therapy. The antidote is unknown.

Interaction:

With the simultaneous use of imatinib with isozyme inhibitory drugs CYP3A4 cytochrome P450, for example, protease inhibitors (indinavir, lopinavir, ritonavir, saquinavir, telaprevir, nelfinavir, boceprevir), antifungal agents of the azole group (incl. ketoconazole, itraconazole, posaconazole, voriconazole), some antibiotics-macrolides (erythromycin, clarithromycin, telithromycin), possibly slowing the metabolism of imatinib and increasing its concentration in the blood plasma.

Caution is necessary when combined use of the drug Imatinib with preparations inhibiting the isoenzymes CYP3A4.

On the contrary, the simultaneous use of drugs that are inducers CYP3A4 (for example, rifampicin, dexamethasone, preparations from St. John's wort perforated, antiepileptic drugs: carbamazepine, oxcarbazepine, phenytoin, phenobarbital, fosphenytoin, primidon) can lead to an acceleration of the metabolism of imatinib and, as a consequence, a decrease in its concentration in the blood plasma.

With the simultaneous use of imatinib and simvastatin, there is an increase in C_mOh and AUC simvastatin in 2 and 3.5 times, respectively, which is a consequence of inhibition CYP3A4 imatinib.

It is advisable to use caution when using imatinib and preparations that are substrates of the isoenzyme CYP3A4 and having a narrow therapeutic range (eg, ciclosporin, pimozide, tacrolimus, sirolimus, ergotamine, fentanyl, terfenadine, bortezomib, docetaxel, quinidine). Imatinib can increase serum concentrations of other drugs metabolized by isoenzyme CYP3A4 (triazolo-benzodiazepines, dihydropyridine, blockers "slow" calcium channels, most of the inhibitors of HMG-CoA reductase, incl. statins).

Imatinib also inhibits isoenzyme CYP2C9 and isoenzyme CYP2C19 in vitro.

Elongation of prothrombin time was observed with the combined use of imatinib with warfarin.

When used simultaneously with coumarin derivatives, short-term monitoring of prothrombin time at the beginning and end of therapy with the drug is necessary, as well as with a change in the dosage regimen of the drug Imatinib.

As an alternative to warfarin, consideration should be given to the use of low molecular weight heparins.

With a combination of the drug Imatinib with chemotherapeutic drugs in high doses, it is possible to develop transient hepatic toxicity in the form of an increase in the level of "liver" transaminases and hyperbilirubinemia.

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

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

When using the drug Imatinib together with metoprolol, isoenzyme substrate CYP2D6, there is a moderate decrease in metoprolol metabolism, accompanied by an increase FROM_mOh and AUC. Given the moderate increase in the effects of drugs that are substrates of the isoenzyme CYP2D6 (eg, metoprolol), when combined with the drug Imatinib, you do not need to change the dosage regimen.

In vitro imatinib inhibits O-glucuronidation of paracetamol / acetaminophen. Care should be taken when prescribing the drug Imatinib together with paracetamol / acetaminophen in view of the possible development in patients of acute hepatic insufficiency with lethal outcome.

In patients after thyroidectomy receiving hormone replacement therapy with levothyroxine sodium, it is possible to reduce its concentration in blood plasma with simultaneous application with imatinib.

Reported on the development of liver damage with simultaneous application imatinib and asparaginase.

Special instructions:

Treatment with drug Imatinib should be carried out only under the supervision of a doctor who has experience working 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 in children with ALL is less than 1 year, the experience with imatinib in children with CML younger than 2 years is limited, experience with imatinib for other indications is limited in patients under 18 years of age. Long-term effects of prolonged exposure to imatinib for growth in children are not known, but since there are reports of growth retardation, careful growth control is recommended in children receiving imatinib.

When using the drug Imatinib it is recommended to conduct a regular clinical blood test and monitor liver function (transaminases,bilirubin, alkaline phosphatase).

Care should be taken to monitor patients with heart and kidney disease. Due to the fact that with the use of the drug Imatinib In 1-2% of cases, a marked fluid retention is noted, it is recommended to regularly monitor the body weight of patients. In the case of a rapid sudden increase in body weight, the patient should be examined and, if necessary, temporarily discontinued therapy with the drug Imatinib and / or prescribe 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 prescribing a drug, patients with liver disease should regularly perform a clinical blood test and determine the "activity" of hepatic enzymes.

Since there are reports of the development of hypothyroidism against the background of the drug Imatinib in patients who have undergone thyroidectomy and who receive substitution treatment with levothyroxine sodium, it is necessary to regularly determine the concentration of thyroid-stimulating hormone in this category of patients.

In patients with hypereosinophilia syndrome and heart disease at the beginning of therapy with the drug Imatinib there are isolated cases of development of cardiogenic shock / left ventricular failure. These undesirable phenomena stop after the introduction of systemic glucocorticosteroids, the adoption of measures aimed at maintaining blood circulation, and the temporary discontinuation of the drug 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. If abnormalities are found at the beginning of therapy, the possibility of prophylactic use of systemic glucocorticosteroids (1-2 mg / kg) for 1-2 weeks should be considered simultaneously with the drug Imatinib.

Bleeding was observed both in the organs of the abdominal cavity and in the liver, depending on the localization of tumor sites.

In patients with inoperable and / or metastatic malignant gastrointestinal stromal tumors, hemorrhages of various locations were noted.

In addition, in the post-marketing period, separate reports were received on cases of vascular ectasia of the antrum of the stomach (GAVE-syndrome), a rare cause of gastrointestinal bleeding, registered in patients with CML, ALL and other diseases.

It is necessary to monitor the state of the gastrointestinal tract in patients with metastatic malignant gastrointestinal stromal tumors (abdominal pain, gastrointestinal bleeding, constipation, etc.) at the beginning and throughout the therapy with imatinib. If necessary, consider the possibility of reversing therapy with the drug. Because of the risk of developing a tumor lysis syndrome, imatinib should be treated with clinically pronounced dehydration and increased uric acid concentrations, if necessary.

During drug therapy Imatinib and at least within 3 months after the use of reliable methods of contraception.

It is possible to increase the level of transaminases or bilirubin in patients with CML, which is controlled by a decrease in the dose of the drug or a temporary interruption in treatment.

Effect on the ability to drive transp. cf. and fur:

Side effects of the drug, such as dizziness and blurred vision,can adversely affect the ability to manage motor vehicles and perform potentially dangerous activities that require increased concentration and speed of psychomotor reactions. In this regard, patients receiving imatinib, there should be increased attention and caution in the management of vehicles and the implementation of potentially hazardous activities. When these undesirable phenomena appear, one should refrain from performing these activities.

Form release / dosage:

Tablets coated with a film coat, 100 mg and 400 mg.

Packaging:

For 10 tablets in Al / Al blister. By 3, 6 or 12 blisters together with instructions for use in a cardboard box.

For 30 (for a dosage of 400 mg) or 90 (for the dosage of 100 mg) tablets in a container of HDPE. Each container contains silica gel. 1 container in a cardboard box with instructions for use.

Storage conditions:

Store at a temperature not exceeding 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003937

Date of registration:07.11.2016

Expiration Date:07.11.2021

The owner of the registration certificate:Heterose Labs LimitedHeterose Labs Limited India

Manufacturer: & nbsp

HETERO LABS, Limited India

MAKIZ-PHARMA, LLC Russia

Representation: & nbspMAKIZ-PHARMA, LLCMAKIZ-PHARMA, LLCRussia

Information update date: & nbsp09.11.2017

Illustrated instructions

Instructions

Imatinib (Imatinib)