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

Imatinib exerts a selective inhibitory effect on the Bz-Abl-tyrosine kinase enzyme,(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 that are formed in patients with a positive in the Philadelphia chromosome with chronic myeloid leukemia and acute lymphoblastic leukemia.

Imatinib selectively inhibits Bcr-Abl-positive colonies derived from blood cells from patients with chronic myelogenous 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 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 dysregulation of platelet growth factors and stem cells,c-Kit receptor and Abl-tyrosine kinase.

When imatinib was used in patients with inoperable and / or metastatic malignant gastrointestinal stromal tumors, there was a significant increase in the overall survival of patients (48.8 months) and disease-free survival (21 months).

Adjuvant therapy with the preparation of gastrointestinal stromal tumors within 1 year reduces the risk of relapse by 89%, increases the survival rate without symptoms (38 months. Imatinib in comparison with 20 months. placebo). Adjuvant therapy with the preparation of gastrointestinal stromal tumors for 3 years leads to a significant increase in overall survival and survival without signs of disease progression compared with therapy for 1 year.

Pharmacokinetics:

The pharmacokinetic parameters of imatinib were evaluated in the dose range from 25 mg to 1000 mg. Pharmacokinetic profiles were analyzed on the first day, and also when equilibrium concentrations of imatinib in plasma were reached on day 7 or 28.

Absorption

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%. In the dose range from 25 to 1000 mg, a direct linear dependence of the AUC value on the dose value was observed.

When taking the drug with a high-fat diet, compared 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 (C_max) by 11%, AUC - by 7.4%) and slowing the rate of absorption (an increase in the time to reach the maximum concentration of imatinib in the blood plasma (T_max) for 1.5 hours).

Distribution

About 95% of imatinib binds to plasma proteins (mainly with albumin and acid alpha-glycoproteins, to a small extent - with lipoproteins).

Metabolism

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

Excretion

It is excreted mainly in the form of metabolites within 7 days after taking one dose: 68% - by the intestine and 13% - by the kidneys. 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 1 time per day, the pharmacokinetic parameters do not change, and the equilibrium concentration of imatinib exceeds the initial concentration by 1.5-2.5 times.

Pharmacokinetics in different groups

In patients older than 65 years, the volume of distribution increases insignificantly (by 12%). For patients with a body weight of 50 kg, the average clearance value of imatinib is 8.5 l / h, and for patients with a body weight of 100 kg, 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 does not depend on sex. Changes in clearance and volume distribution of imatinib with simultaneous use with other drugs are insignificant and do not require dose changes.

Pharmacokinetics in children

In children and adolescents under the age of 18, as in adults, there is a rapid absorption of the drug when ingested.AUC in this group of patients in a dose range of 260 and 340 mg / m² is similar to that in adults in the dose range of 400 mg and 600 mg, respectively. When comparing the values of AUC in children and adolescents₍₀_-₂₄₎on the first and eighth days after repeated administration of the drug at 340 mg / m²Once a day, the increase in the value of this indicator is observed 1.7 times, indicating the cumulation of imatinib.

Pharmacokinetics in renal dysfunction

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

When imatinib is used in patients with mild or moderate impairment of renal function (creatinine clearance> 30 ml / min), the drug exposure in plasma is increased by a factor of 1.5 - 2.0, corresponding to an increase in the concentration of acid alpha-glycoproteins (the main proteins of the plasma binding with imatinib). Since the drug is slightly excreted by the kidneys, the clearance of free imatinib was the same for healthy volunteers and patients with impaired renal function. 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 chronic myeloid leukemia (Ph + XML) in children and adults;

- Positive for the Philadelphia chromosome (Ph +) XML in the chronic phase with failure of prior therapy with interferon alpha or in the phase of acceleration, or blast crisis in children and adults;

- The first diagnosed positive for the Philadelphia chromosome acute lymphoblastic leukemia (Ph + OLD) 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 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 imatinib or any other component of the drug;

- Children under 2 years of age (effectiveness and safety have not been established to date);

- Pregnancy and the period of breastfeeding.

Carefully:

If you have any of the listed diseases before taking the drug, be sure to consult a doctor.

Caution should be used to administer Imatin to patients with severe hepatic impairment, severe renal dysfunction, cardiovascular disease or risk factors for heart failure, and regular hemodialysis.

When used simultaneously with preparations inhibiting the isofsis CYP3A4, strong inducers of the isoenzyme CYP3A4, with preparations that are substrates of the isoenzyme CYP3A4, paracetamol, warfarin (see the section "Interaction with other drugs").

Pregnancy and lactation:Contraindicated the use of imatinib during pregnancy and during breastfeeding.

Dosing and Administration:

Inside at the time of food intake, washed down with a full glass of water to reduce the risk of developing gastrointestinal disorders.

Doses of 400 mg and 600 mg per day are 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 resulting suspension is ingested immediately after preparation. After opening the capsules, wash hands immediately.

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

In chronic myelogenous leukemia (XML) the recommended dose of the drug Imatib 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.

In the absence of severe side effects and neutropenia or thrombocytopenia not associated with leukemia, a dose increase 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 accelerated phase and with a blast cry.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 the dosing regimen in children over 2 years of age is based on body surface area. Doses of 340 mg / m²per day are recommended in children with chronic phase XML and 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 + ORL, the recommended dose of Imatin is 600 mg per day.

With inoperable and / or metastatic malignant gastrointestinal stromal tumors, MDS / MPD the recommended dose of Imatin 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 Imatinb from 400 mg to 600 mg or up to 800 mg is possible.

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

When the drug is used as a Adjuvant therapy in 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 is not established.

With inoperable, recurrent and / or metastatic bulging dermatofibrosarcoma the recommended dose of Imatin is 800 mg per day. In CM in the absence of D816V c-K.it mutation, the recommended dose of Imatin is 400 mg per day. With an unknown mutational status and insufficient effectiveness of previous therapy, the recommended dose is 400 mg per day.

In CM caused by an abnormal FIP1L1-PDGFR α-tyrosine kinase, resulting from the fusion of the Fip likel and PDGFR genes, 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 hypereosinophilic syndrome and / or chronic eosinophilic leukemia (HES / 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. Treatment with the drug is carried out as long as the clinical effect remains.

Patients with impaired hepatic function

Because the imatinib Metabolized mainly in the liver, patients with mild, moderate or severe hepatic impairment should be prescribed Imatinb 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 who require systematic hemodialysis, treatment with Imatib should begin with a minimum effective dose of 400 mg once daily, being careful. With intolerance to Imatin, 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, 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 increasing bilirubin concentration and transaminase activity 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 1.5xVGN and the activity of "hepatic" transaminases to less than 2,5хVGN.

Therapy with Imatinb is resumed 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 / m² per 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. In patients with CM and hypereosinophilic syndrome and / or chronic eosinophilic leukemia (HES / CAL) due to abnormal FIP1L1-PDGFR α-tyrosine kinase (initial dose of Imatinb 100 mg), in the event of an absolute decrease in the number of neutrophils <1000 / μL and / or platelet count < 50000 / μL is recommended:

1. abolish the preparation of Imatinum until the absolute amount of neutrophils is ≥1500 / μL and platelets ≥75,000 / μL;

2. to resume treatment with Imatinb in a dose used before the interruption of therapy.

In the chronic phase of CML in children and adults (initial dose for adults - 400 mg, for children - 340 mg / m²), malignant gastrointestinal stromal tumors, MDS / MPD, SM and HES / HAL in adult patients (initial dose for adults is 400 mg) in the case of a decrease in the absolute number of neutrophils <1000 / μL and / or the number of platelets <50000 / μL, it is recommended:

1. abolish the preparation of Imatinum until the absolute amount of neutrophils is ≥1500 / μL and platelets ≥75,000 / μL;

2. to resume treatment with Imatinb in a dose used before the interruption of therapy.

3. If the number of neutrophils <1000 / μL and / or the number of platelets <50000 / μL is repeated again, the actions indicated in paragraph 1 should be repeated, and then the treatment with Imatinb should be resumed at 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 in Ph + ALL in adult patients (initial dose for adults - 600 mg, for children - 340 mg / m²) in the case of a decrease in the absolute number of neutrophils <500 / μL and / or the number of platelets <10,000 / μL after one or more months of treatment, it 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 Imatib to 400 mg (in 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 the preparation of Imatinum until the absolute number of neutrophils is ≥1000 / μL and platelets ≥20000 / μL; then resume treatment with the drug Imatib at a dose of 300 mg (in children - 260 mg / m²).

With inoperable, recurrent and / or metastatic swelling dermatofibrosarcoma (the initial dose of Imatin 800 mg) in the case of a decrease in the absolute number of neutrophils <1000 / μL and / or platelet count <50000 / μL is recommended:

1. abolish the preparation of Imatinum until the absolute amount of neutrophils is ≥1500 / μL and platelets ≥75,000 / μL;

2. to resume treatment with Imatinb in a dose of 600 mg.

If the number of neutrophils is less than 1000 / μL and / or the number of platelets is less than 50,000 / μL, repeat the actions indicated in paragraph 1, and then resume treatment with Imatinib at a reduced dose of 400 mg.

Side effects:

The safety profile of imatinib has been well studied. Most patients with the drug experience some of the undesirable phenomena (AE). The most frequent AE (> 10%) associated with taking the drug were: neutropenia, thrombocytopenia, anemia, headache, dyspepsia, swelling, weight gain, nausea, vomiting, diarrhea, myalgia, muscle cramps, rash, weakness, pain in stomach. Most of these AEs were mild or moderately severe. Only 2 to 5% of patients discontinued imatinib therapy because of the development of AEs.

Types of AEs and the frequency of their development are similar when imatinib is taken by adults and children with leukemia.

Myelosuppression, AE on the part of the gastrointestinal tract (GIT), edema and rash occur when imatinib is used in both XML and malignant stromal tumors of the gastrointestinal tract. Patients with XML often develop myelosuppression, and patients with malignant stromal tumors of the gastrointestinal tract are more likely to develop gastrointestinal and intrapuinal bleeding. Other disorders of the gastrointestinal tract, such as gastrointestinal obstruction, perforation and ulceration, occur more often with stromal GI tract. Other serious AEs with imatinib are hepatotoxicity, acute renal failure, hypophosphatemia, respiratory system disorders, tumor lysis syndrome and growth retardation in children.

Combined side effects, such as pleural effusion, ascites, pulmonary edema and a rapid increase in body weight with or without peripheral edema, can be qualified as "fluid retention" and in some cases reach serious (including life-threatening) levels.

It is possible to adjust the dose of the drug depending on the severity of AE, right up to the withdrawal of the drug.

In patients with XML and with inoperable and / or metastatic malignant stromal tumors of the gastrointestinal tract, the following undesirable phenomena listed below for organs and systems with the frequency of their occurrence were noted: very often (≥1 / 10), often (≥1 / 100 <1 / 10), infrequently (≥1 / 1000 <1/100), rarely (≥1 / 10000 <1/1000), very rarely (<1/10000), including individual messages:

Infectious and parasitic diseases: infrequently - herpes simple, herpes zoster, nasopharyngitis, pneumonia¹, 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 of the blood and lymphatic system: very often-neutropenia, thrombocytopenia, anemia; often - paitsitopenia, 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,increased or decreased appetite, hypophosphatemia, dehydration, hyperuricemia, gout, hypercalcemia, hyperglycemia, hyponatremia; rarely, hyperkalemia, hypomagnesemia.

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

Disturbances from the nervous system: very often - headache²; often - dizziness, paresthesia, taste disorder, hypoesthesia; infrequently - migraine, drowsiness, fainting, peripheral neuropathy, memory impairment, sciatica, restless legs syndrome, tremor, hemorrhagic stroke; rarely increased intracranial pressure, convulsions, optic neuritis.

Disturbances on the part of the organ of sight: often - edema of the eyelids, increased tearing, hemorrhage under the conjunctiva, 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.

Hearing disorders and labyrinthine disorders: infrequently -verthigo, tinnitus, hearing loss.

Heart Disease: infrequent-palpitation, chronic heart failure³, pulmonary edema, tachycardia, "hot flashes"⁴; rarely - arrhythmias, atrial fibrillation, sudden cardiac arrest; myocardial infarction, stenocardia, pericardial effusion.

Vascular disorders: infrequently - hemorrhages⁴; rarely - hematomas, subdural hematomas, cold extremities, increased blood pressure, lower blood pressure, Raynaud's syndrome.

Disturbances from the respiratory system, chest, mediastinum: often - nosebleeds, dyspnea, cough; infrequent pleural effusion⁵, pain in the pharynx or larynx, pharyngitis; rarely - pleural pain, pulmonary fibrosis, pulmonary hypertension, pulmonary hemorrhage.

Disorders from the digestive system: very often - nausea, vomiting, diarrhea, dyspepsia, abdominal pain⁶; often-abdominal bloating, flatulence, constipation, gastro-esophageal reflux, dryness of the oral mucosa, gastritis; infrequently - stomatitis, ulceration of the oral mucosa, gastrointestinal bleeding⁷, belching, melena, esophagitis, ascites, stomach ulcer, vomiting of blood, cheilitis,dysphagia, pancreatitis; rarely - colitis, paralytic / obturation intestinal obstruction, inflammation of the intestine.

Disturbances from the liver and bile ducts: often increase the activity of "liver" enzymes; infrequently - jaundice, hepatitis, hyperbilirubinemia; rarely - liver failure⁹, necrosis of the liver⁹.

Disturbances from the skin and subcutaneous tissues: very often periorbital edema, dermatitis, eczema, skin rash; often - puffiness of the face, itching, erythema, dry skin, alopecia, night sweats, photosensitivity reactions; infrequently - pustular rash, petechiae, increased sweating, urticaria, ecchymosis, increased predisposition to the formation of hematomas, hypotrichosis, hyperpigmentation / hypopigmentation of the skin, exfoliative dermatitis, nail damage folliculitis, psoriasis, purpura, bullous rash; rarely acute febrile neutrophilic dermatosis (Sweet syndrome), discoloration of the nails, angioedema, erythema multiforme, leukocytoclastic vasculitis, Stevens-Johnson syndrome, acute generalized pustular exanthema.

Disturbances of musculoskeletal and connective tissue: very often - muscle spasms and cramps, musculoskeletal pain, including myalgia, arthralgia, bone pain⁸; often, swelling in the joints; infrequently-the intensity of muscles and joints; seldom-muscular weakness, arthritis; frequency is unknown - growth retardation in children.

Disorders from the kidneys and urinary tract: infrequently - kidney pain, hematuria, acute renal failure, frequent urination.

Violation of the endocrine system, genital organs and mammary glands: infrequently - gynecomastia, erectile dysfunction, menorrhagia, menstrual disorders, sexual dysfunction, pain in the nipples, enlargement of the mammary glands, swelling of the scrotum.

General disorders and disorders at the site of administration: very often - fluid retention and swelling, increased fatigue, weight gain; often - weakness, fever, anasarca, chills, trembling, weight loss; infrequently - chest pain, general malaise.

Laboratory and instrumental research: infrequently - increased activity of alkaline phosphatase, creatine phosphokinase, lactate dehydrogenase and creatinine levels in the blood serum; rarely - increased activity of amylase in the blood plasma.

¹Pneumonia is most often observed in patients with CML in the phase of acceleration, blast crisis and with inoperable and / or metastatic malignant stromal tumors of the gastrointestinal tract;

²Headache was most often noted in patients with inoperable and / or metastatic gastrointestinal malignant tumors;

³Undesirable heart events, including chronic heart failure, were more common in patients with XMJI in the acceleration phase and blast crisis than those with XMJT in the chronic phase (duration of follow-up was 1 year);

⁴"Tides" most frequently observed in patients with unresectable and / or metastatic malignant gastrointestinal stromal tumors;

bleeding (haematomas, hemorrhages) are most often observed in patients with XMJI in the phase of acceleration, blast crisis and with inoperable and / or metastatic and malignant stromal GI tract tumors;

⁵Pleural effusion is more often noted in patients with XMJI in the phase of acceleration and blast crisis compared with patients with XMJI in the chronic phase (duration of follow-up is 1 year);

^6/7Abdominal pain and gastrointestinal hemorrhage were most often observed in patients with inoperable and / or metastatic gastrointestinal malignant tumors;

⁸Musculoskeletal pain, including myalgia, arthralgia, bone pain, was more common in patients with CML compared with patients with inoperable and / or metastatic gastrointestinal malignant tumors;

⁹Individual cases of hepatic insufficiency and liver necrosis have been reported.

When imatinib was used in clinical practice, as well as during additional clinical trials, the following AEs were listed, listed below for organs and systems, indicating the frequency of their occurrence: very often (≥1/10), often (≥1 / 100 <1/10) , infrequently (≥1 / 1000 <1/100), rarely (≥1 / 10000 - <1/1000), very rarely (<1/10000), including individual messages.

Disturbances from the nervous system: infrequently - edema of the brain.

Disturbances on the part of the organ of sight: rarely - vitreous hemorrhage.

Violations from the heart and blood vessels: infrequently - thrombosis / embolism; rarely pericarditis; cardiac tamponade; very rarely - anaphylactic shock.

Disturbances from the respiratory system, chest, mediastinum: infrequent - acute respiratory failure¹, interstitial pneumonia.

Disorders from the digestive system: infrequently - ileus (intestinal obstruction), bleeding from the tumor of the gastrointestinal tract, necrosis of the tumor of the gastrointestinal tract, perforation of the gastrointestinal tract²; rarely - diverticulitis.

Disturbances from the skin and subcutaneous tissues: infrequently - palmar-plantar erythrodysesthesia; rarely -hehenoid keratosis, red flat lichen; very rarely - toxic epidermal necrolysis; frequency unknown - drug rash with eosinophilia and systemic symptoms.

Disturbances from the osteomuscular and connective tissue: rarely avascular necrosis / necrosis of the head of the femur, rhabdomyolysis / myopathy.

Violations of the genitals: infrequent - decreased potency; very rarely - women bleed from the cyst of the yellow body / ovary.

¹There are some reports of the development of severe acute respiratory failure with a fatal outcome in patients with severe infectious diseases, severe neutropenia and other serious concomitant diseases.

²Individual cases of development of perforations of the gastrointestinal tract with lethal outcome were reported.

Description of individual unwanted drug reactions

Inhibition of hematopoiesis

The frequency of oppression of hematopoiesis and the degree of its expression were maximal when the drug was used in high doses and, apparently, depended on the stage of CML. In general, the oppression of hematopoiesis against imatinib in patients with CML was reversible and in most cases did not require the drug to be withdrawn or its dose reduced. The withdrawal of the drug was required in a small number of cases. Also observed were such phenomena as pancytopenia, lymphoma and oppression of hematopoiesis.

Hemorrhage / bleeding

The most frequent clinically significant bleeding were bleeding from the gastrointestinal tract. Most often they appeared in patients with advanced stages of CML and in patients with malignant stromal tumors of the gastrointestinal tract, in which they can be a consequence of the underlying disease (bleeding from the tumor due to tumor necrosis). In patients with CML, in which hematogenesis was suppressed already before the start of treatment, in the course of treatment, hemorrhages in the central nervous system or gastrointestinal tract are also often noted. It is well established that in patients with leukemia with acute development of the disease bleeding / hemorrhage caused by thrombocytopenia or thrombocytopathy often occurs.

Swelling and fluid retention

Edema is a frequent side effect of imatinib. The incidence of edema in patients receiving imatinib for all indications, is more than 50%. The frequency and severity of edema depends on the dose and, apparently, correlates with the concentration of the drug in the blood plasma. Most often there are periorbital edema, with a slightly lower frequency - swelling of the lower extremities. Specific treatment is usually not required. In patients with edema and fluid retention, heart failure is rare. In patients with advanced stages of XMJI, the incidence of heart failure was higher than in patients of other categories, which can be explained by their weakened state as a whole. The same trend was observed with regard to renal failure in patients with edema and fluid retention. Most patients with edema and fluid retention were elderly (> 65 years).

Rash and severe skin undesirable reactions

In a number of patients who received imatinib, there was a generalized erythematous, spotty-papular and itchy rash that could pass by itself,despite continued treatment with the drug. Some patients had itching, not accompanied by a rash; in a number of cases, there was erythroderma. A rash was noted in about a third of all patients who received imatinib for all indications. Often the rash is accompanied by itching and, as a rule, manifests itself in the form of erythematous, patchy-papular lesions on the forearm, trunk or face. Although in most cases the rash is mild and goes away without treatment, in more severe cases it may be necessary to temporarily or completely discontinue the drug. As a rule, the severity of the rash decreases after the appointment of antihistamines and glucocorticosteroids for topical application. In some cases, use glucocorticoid drugs for systemic use.

Hepatotoxicity

The drug may have a toxic effect on the liver. Disorders of biochemical indicators of liver function, as a rule, consists in a slight increase in the activity of aminotransferases and an increase in serum bilirubin concentration. The toxic effect on the liver usually manifests itself during the first two months of treatment, but in a number of cases it manifested itself 6-12 months after the start of treatment.As a rule, after the drug is discontinued biochemical parameters of the liver function normalize within 1 to 4 weeks.

Were noted cases development of cytolytic and cholestatic hepatitis and liver failure, in some cases, accompanied by a fatal outcome.

Obstruction, perforation or ulcer of the stomach or intestine

A small proportion of patients who received imatinib, ulceration of the gastrointestinal tract was noted, which in some cases may be a consequence of the local irritating effect of imatinib. Hemorrhagic necrosis of the tumor, as well as obstruction and perforation of the gastrointestinal tract, were most often observed in patients with malignant stromal tumors of the gastrointestinal tract. In the case of metastatic stromal tumors of the gastrointestinal tract, tumor necrosis may occur against a background of a tumor response, which in rare cases leads to perforation. Gastrointestinal obstruction most often occurred in patients with malignant stromal tumors of the gastrointestinal tract, in which its cause can serve as metastases or adhesions that have arisen as a result of an earlier operation on the digestive tract (if the drug is used as a means of adequate therapy).Severe adverse events on the part of the respiratory system Severe (sometimes fatal) AEs have been observed with imatinib, namely: acute respiratory failure, pulmonary hypertension, interstitial lung disease and pulmonary fibrosis. The concomitant pathology of the cardiovascular or respiratory systems can aggravate the severity of AEs.

If any of the side effects listed in the manual are aggravated, or if you notice any other side effects not listed in the instructions, tell your doctor.

Overdose:

The experience of using Imatin in doses exceeding therapeutic limits is limited. In clinical practice, there have been cases of imatinib overdose. In general, the outcome of the overdose was favorable (there was an improvement in the patients' condition). Antidote to Imatinib is not known. In case of an overdose, medical supervision and symptomatic therapy are recommended.

Overdose in adults:

When taking the drug Imatinib at a dose of 1200-1600 mg for 1-10 days, nausea, vomiting, diarrhea, rash, erythema, swelling, mostly face, increased fatigue, muscle spasms, thrombocytopenia, abdominal pain, headache, decreased appetite.

When imatinib at a dose of 1800-3200 mg (the highest dose is 3200 mg per day for 6 days), weakness, myalgia, an increase in the activity of creatine phosphokinase, bilirubin concentration, and gastrointestinal pain were noted. When imatinib was administered 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 imatinib in a dose of 8-10 g, vomiting and gastrointestinal pain were noted once.

Overdose in children and adolescents:

When taking imatinib at a dose of 400 mg, a 3-year-old child experienced vomiting, diarrhea, and anorexia. In another case, when imatinib was taken at a dose of 980 mg, a diarrhea and a decrease in the number of leukocytes were observed once in a child aged 3 years.

Interaction:

With the simultaneous use of the drug Imatib with preparations that inhibit the cytochrome P450 isoenzyme CYP3A4 (ketoconazole, itraconazole, erythromycin, clarithromycin), there may be a slowdown in the metabolism of imatinib and an increase in its concentration in the blood plasma.Caution is necessary when combined with the use of Imatinb with inhibitor preparations of CYP3A4 isoenzymes. In contrast, the simultaneous use of drugs that are inducers of the isoenzyme CYP3A4 (for example, dexamethasone, rifampicin, antiepileptic drugs: carbamazepine, oxcarbazepine, phenytoin, phenobarbital, fosphenytoin, primidon or drugs based on St. John's wort) can lead to an acceleration of the metabolism of imatinib and, as a consequence, reduce its concentration in the blood plasma.

With the simultaneous use of imatinib and simvastatin, an increase in C_maxand AUC in 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 Imatin and preparations that are substrates of the CYP3A4 isoenzyme and have a narrow range of therapeutic concentration (for example, ciclosporin and pimozide). The drug Imatib may increase serum concentrations of other drugs metabolized by the isoenzyme CYP3A4 (triazolobenzodiazepines, dihydropyridine, blockers of "slow" calcium channels, most inhibitors of HMG-CoA reductase, including statins). Imatinib also inhibits the isoenzyme CYP2C9 and the isoenzyme CYP2C19 in vitro. When the combination of the drug Imatib with warfarin, prolonged prothrombin time was observed. 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 when the dosage regimen of the preparation is changed. As an alternative to warfarin, consideration should be given to the use of low molecular weight heparins.

With the combination of Imatin and chemotherapeutic drugs in high doses, it is possible to develop transient hepatic toxicity in the form of an increase in the activity of "liver" 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 using the preparation of Imatinib 400 mg twice a day together with metoprolol, the substrate of the isoenzyme CYP2D6, there was a moderate decrease in metoprolol metabolism, accompanied by an increase in C_maxand AUC by approximately 21%.Given the moderate increase in the effects of drugs that are substrates of the isoenzyme CYP2D6 (eg, metoprolol), when combined with imatinib, a change in the dosing regimen is not required.

In vitro imatinib inhibits O-glucuronation of paracetamol. A case of development in the patient of acute hepatic insufficiency with a lethal outcome is described with simultaneous application of imatinib and paracetamol. Caution must be exercised when applying imatinib together with paracetamol.

Special instructions:

Treatment with Imatib should be done 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, and inhale the powder of the drug.

The experience of treatment with Imatib in children with XML younger than 2 years is limited, the experience of using the drug for other indications is limited in patients under 18 years of age.

The long-term effects of prolonged exposure to Imatinb on growth in children are unknown. But, since there are reports of growth retardation, careful growth control is recommended in children using imatinib. When using the drug Imatib, it is recommended to regularly perform clinical blood tests and monitor liver function (transaminase, bilirubin, alkaline phosphatase).

Mass monitoring of patients with heart and kidney disease should be ensured. In connection with the fact that with the use of Imatin in 1-2% of cases there is a pronounced fluid retention, 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 Imatin 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 the drug was used, the patient died with a blast crisis and complex symptomatology: pleural effusion, congestive heart failure and kidney failure.

When the drug is used, patients with liver diseases 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 substitution treatment with levothyroxine sodium, the concentration of thyroid-stimulating hormone must be regularly determined 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 cancellation of Imatin. 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 should consider the possibility of preventive use of systemic glucocorticosteroids (1-2 mg / kg) for 1-2 weeks simultaneously with imatinib.

In patients with inoperable and / or metastatic malignant gastrointestinal stromal tumors in clinical studies of bleedingdifferent localizations were noted in 12.9% of cases; gastrointestinal bleeding was noted in 8 patients (5.4%), bleeding from tumor foci in 4 patients (2.7%).

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

It is necessary to monitor the state of the gastrointestinal tract in patients with metastatic malignant gastrointestinal stromal tumors at the beginning of imatinib therapy.

During therapy with Imatin and, at least 3 months after, reliable methods of contraception should be used.

A marked increase in the activity of "hepatic" transaminases or bilirubin was noted in less than 3% of patients with XML and was usually controlled by a decrease in the dose of the drug or a temporary interruption of treatment (the average duration of such episodes was about 1 week).

Due to the risk of development of tumor lysis syndrome before the appointment of the drug, Imatib should, if necessary, correct clinically pronounced dehydration and an elevated uric acid level in patients.

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 vehicles and perform potentially dangerous activities that require increased concentration and speed of psychomotor reactions. In this regard, patients taking the drug Imatib, should show increased attention and caution when driving vehicles and performing potentially hazardous activities.

Form release / dosage:Capsules 50 mg, capsules 100 mg.

Packaging:

Capsules 50 mg:

- 10 capsules are placed in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered. 3 contour squares are placed together with instructions for medical use in a cardboard box.

- For 30 capsules are placed in vials of polymeric materials for medicines, sealed with a plastic lid with control of the first opening or without it. 1 bottle is placed together with instructions for medical use in a cardboard box.

Capsules 100 mg:

- For 12 capsules are placed in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered. By 2, 3, 4, 8, 10 or 15 contour mesh packages are placed together with the instruction for medical use in a cardboard pack.

- 24, 36, 48, 96, 120 or 180 capsules are placed in vials of polymeric materials for medicinal products sealed with a plastic lid, with or without first opening. On 1 bottle together with the instruction on medical application place in a cardboard pack.

Storage conditions:In a dry, protected from light place at a temperature of no higher than 25 ° C. Keep out of reach of children.

Shelf life:2 years. Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002040

Date of registration:10.04.2013 / 24.10.2016

Expiration Date:10.04.2018

The owner of the registration certificate:FARM-SYNTHESIS, CJSC FARM-SYNTHESIS, CJSC Russia

Manufacturer: & nbsp

Company DEKO, LLC Russia

Information update date: & nbsp10.11.2017

Illustrated instructions

Instructions

Imatib (Imatib)