Imatinib medak - instructions for use, doses, side effects, contraindications

Imatinib selectively inhibits the activity of the Bru-Abl-tyrosine kinase enzyme and a number of tyrosine kinase receptors: Kit (SCF table cell factor receptor,(DDR1 and DDR2), colony stimulating factor (CSF-IR), and platelet-derived platelet growth factors (PDGFR-a and PDGFR-P). Imatinib suppresses cellular reactions caused by the activation of these receptors.

The inhibitory activity of imatinib against tyrosine kinases, in particular Bros-ALY tyrosine kinase, has been confirmed in studies on cell lines in vitro and in vivo. Selectively inhibits proliferation and induces apoptosis of the cell lines that express Bs-Abl tyrosine kinase, including immature leukemia cells in patients with chronic myeloid leukemia (XML) positive in the Philadelphia chromosome and acute lymphoblastic leukemia (ALL).

On in vivo laboratory models, the drug exhibits antitumor activity in monotherapy of neoplasms containing Bs-Abl-positive colonies from blood cells of patients with CML.

It is known that the activation of the c-kit receptor tyrosine kinase and receptors for platelet growth factors can underlie the pathogenesis of systemic mastocytosis. Activation of receptors to platelet growth factors or Abl-fragment of tyrosine kinases can cause the development of both myelodysplastic / myeloproliferative diseases, and hypereosinophilic syndrome and chronic eosnophilic leukemia,as well as bulging dermatofibrosarcoma.

In vitro imatinib inhibits proliferation and induces apoptosis of cells of gastrointestinal stromal tumors (GISO) expressing tyrosine kinias with the c-K mutation of the it-receptor.

Pharmacokinetics:

Pharmacokinetic parameters were studied in the dose range from 25 mg to 1000 mg of imatinib, the pharmacokinetic profile was analyzed on the first day, and also when equilibrium concentrations in plasma were reached (days 7, 28).

Suction. After oral administration, the bioavailability of imatinib is 98% on average. The area variation coefficient under the concentration-time curve (AUC) is characterized by considerable variability from patient to patient. At simultaneous reception of a preparation with the food characterized by the high maintenance of fats, in comparison with reception on an empty stomach, there is an insignificant decrease in a degree (decrease of value of the maximum concentration in a blood plasma on 11% and values AUC on 7,4%) and slowing down of speed of absorption the maximum concentration in the plasma for 1.5 hours). However, the effect of previous surgical operations on the gastrointestinal fact on imatinib absorption was not studied.

Distribution. At clinically significant concentrations, binding to plasma proteins is about 95% (mainly with albumin and acid alpha-glycoproteins, to a small extent - with lipoproteins).

Metabolism. Imatinib metabolized mainly in the liver; 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 starting material. The AUC value for this metabolite is 16% of the Imatinib AUC; binding to plasma proteins is analogous to this parameter of imatinib.

Excretion. About 81% of the taken single dose of imatinib is excreted as metabolites within 7 days after admission (68% with feces, 13% with urine). In an unchanged form, about 25% of the dose is excreted (20% with feces, 5% with urine).

The half-life of imatinib after taking a single dose inwards in healthy volunteers is about 18 hours. In the dose range from 25 mg to 1000 mg, the dependence of the AUC value on the dose value is linear. When taking repeated doses, prescribed once a day, the pharmacokinetic parameters of imatinib do not change; the value of the equilibrium concentration exceeds the value of the initial concentration by a factor of 1.5 to 2.5.

In patients with gastrointestinal stromal tumors (GISO) at a dose of imatinib 400 mg / day, the equilibrium concentration is 1.5 times higher in the same indicator in XMJI patients.

The presence of liver metastases in patients with GISD is a risk factor for disrupting the normal metabolism of imatinib due to the risk of developing liver failure. In patients with XML, the volume of distribution increases slightly with age (about 12% in patients older than 65 years), but these changes are not considered clinically significant. Imatinib's clearance correlates with body weight (MT): in patients with MT 50 kg the average value of this indicator is 8.5 l / h, in patients with MT 100 kg - 11.8 l / h. However, these changes are not considered significant and are not the basis for dose adjustment depending on the patient's body weight. The pharmacokinetics of imatinib does not depend on the sex of the patient.

In children and adolescents under the age of 18, as in adult patients, after oral administration imatinib quickly absorbed. Dependence of imatinib plasma concentration on dose after oral administration of the drug in the dose range from 260 to 340 mg / m² per day is similar to this indicator in adults at doses from 400 to 600 mg / m² in a day. Comparison of AUC values₀_-₂₄on days 1 and 8 after repeated administration of imatinib at doses of 340 mg / m²a day showed a 1.7-fold cumulation of the drug.

Based on the combined population pharmacokinetic analysis in children with hematological diseases, it was shown that the clearance of imatinib is directly proportional to the surface area of the body, other demographic parameters (age, body weight and body mass index) have no clinically significant effect on the imatinib exposure.

Patients with impaired hepatic function: in patients with varying degrees of impaired liver function, the mean AUC values do not increase.

Imatinib and its metabolites are excreted by the kidneys only in a small volume, in patients with mild to moderate renal impairment, the concentration of the drug in plasma is slightly increased; while an increase in the exposure of the drug in the plasma is 1.5-2 times accompanied by a 1.5-fold increase in the concentration of alpha-glycoproteins (the main plasma proteins that bind to imatinib). Because the imatinib is excreted by the kidneys slightly, the clearance of free imatinib in patients with normal and impaired renal function does not differ significantly.

Indications:

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

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

- 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 platelet-derived growth factor receptor gene rearrangements in adult patients;

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

- hypereosionophilic syndrome and / or chronic eosinophilic leukemia in adults with positive or negative abnormal FIP1L1-PDGFR 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 other components of the drug;

- Children under 2 years of age (efficacy and safety not established);

- Pregnancy and the period of breastfeeding.

Carefully:

Patients with severe hepatic insufficiency, severe impairment of kidney function (creatinine clearance less than 30 ml / min), cardiovascular disease or in the presence of risk factors for heart failure, as well as in the regular procedure of hemodialysis.

Patients with hereditary lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome, with simultaneous use with strong inducers of the isoenzyme CYP3A4, paracetamol, warfarin (see section "Interaction with other drugs").

Pregnancy and lactation:

Pregnancy: there is currently 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 should use reliable methodscontraception.

Lactation: imatinib and its metabolites are excreted in breast milk. Due to the lack of data on the effect of imatinib on newborns, women taking imtinib should stop breastfeeding.

Dosing and Administration:

The drug should be taken orally during a meal, washed down with a full glass of water to reduce the risk of developing gastrointestinal disorders.

Doses of 400 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 should be taken in a diluted form; the contents of the capsules are diluted with water or apple juice. The resulting suspension should be taken immediately after preparation.

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

For XML:

- In adult patients with XML the recommended dose of Imatinib medak 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 question of increasing the dose from 400 mg to 600 mg or from 600 mg to a maximum of 800 mg per day (2 times a day400 mg) can be considered provided there are no serious adverse reactions and severe neutropenia or thrombocytopenia not associated with the underlying disease. Such a dose increase may be necessary in the following cases: progression of the disease (at any stage); no satisfactory hematologic response after 3 months of treatment; insufficient cytogenetic response after 12 months of therapy; loss of previously hematologic and / or cytogenetic response. After increasing the dose, careful clinical observation of patients is necessary because of the potential risk of adverse reactions.

- In children older than 2 years the dose is calculated based on the surface area of the body. In patients with CML in the chronic phase and in the acceleration phase, the recommended dose is 340 mg / m² per day. The total daily dose should not exceed 600 mg. The daily dose should be taken once or split into two doses - in the morning and in the evening.

In the absence of severe adverse reactions to the drug and severe, neutropenia or thrombocytopenia not associated with leukemia, in some cases a dose increase from 340 mg / m² up to 570 mg / m² per day (in any case not more than 600 mg per day), namely: with the progression of the disease (in any phase); no satisfactory hematologic response after 3 months of treatment; absence of a cytogenetic response at 12 months from the start of treatment; loss of previously achieved hematologic and / or cytogenetic response. After increasing the dose, patients need to ensure thorough clinical observation because of the increased risk of adverse reactions.

With Ph + ALL:

The recommended dose of Imatinib medac in adult patients is 600 mg per day. In this dose, the drug is effective and safe when used in combination chemotherapy regimens in the phase of induction, consolidation and maintenance therapy in adult patients with newly diagnosed PH + ALL. At all phases of therapy, the patient should be provided with a clinical observation of a hematologist. The duration of treatment depends on the chosen chemotherapy regimen, while, as a rule, the longer it is applied imatinib, the better the results of treatment can be achieved.

With relapsing or refractory Ph + ALL, it is recommended that Imatinib monotherapy be administered at a dose of 600 mg per day until the disease progresses.

In myelodysplastic / myeloproliferative diseases (MDD / MPZ): The recommended dose of Imatinib medac in adults is 400 mg / day.

With systemic mastocytosis (CM):

The recommended dose of imatinib medac in patients with no D816V c-Kit mutations is 400 mg per day. In systemic mastocytosis caused by abnormal FIP1L1-PDGFRa-tyrosine kinase and accompanied by eosinophilia, the recommended initial dose is 100 mg per day. With insufficient effectiveness and no significant side effects, an increase in the dose from 100 mg to 400 mg per day is possible. With an unknown mutational status and insufficient effectiveness of previous therapy, the recommended dose is 400 mg per day.

With hypereosinophilic syndrome and / or chronic eosinophilic leukemia (HES / HAL): In HES / HAL in adults, the recommended dose is 400 mg per day. In patients with HES / HAL, caused by an abnormal FIP1L1-PDGFR atrorosine 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 per day is possible. Treatment is carried out as long as the clinical effect remains.

With inoperable and / or metastatic gastrointestinal stromal tumors (GISO):

The recommended dose of imatinib medac is 400 mg per day. With insufficient effectiveness and no significant side effects, an increase in the dose to 600 mg or up to 800 mg is possible. Treatment with imatinib is carried out to the first signs of progression of the disease.

When Imatinib is administered medaka in adjuvant therapy in patients with GISO, the recommended dose is 400 mg per day. The optimal duration of adjuvant therapy has not been established. The minimum duration of treatment is 3 years.

With inoperable, recurrent and / or metastatic swelling dermatofibrosarcoma (VDFS):

The recommended dose is 800 mg per day.

Recommendations for correcting the dosing regimen Imatinib medak with the development of side effects

Non-hematological adverse reactions: in the case of severe non-hematologic reactions with imatinib, treatment should be suspended until these reactions are resolved, after which the resumption of therapy should be considered taking into account the severity of the side effects.

If the upper limit of the norm (VGI) is exceeded by more than 3 times the concentration of bilirubin or the activity of "hepatic" transaminases is more than 5 times, the medication should be interrupted by Imatinib before the decrease of these parameters is below 1.5 VGN and below 2.5 VGN, respectively, after which the treatment with the drug can be continued in a reduced dose. In adult patients, the daily dose should be reduced from 400 mg to 300 mg, or from 600 mg to 400 mg, or from 800 mg to 600 mg; children should reduce the dose with 340 mg / m²up to 260 mg / m² per day.

Adverse reactions from the hematopoietic system: recommendations for dose reduction and interruption of treatment for severe neutropenia and trobocytopenia are given in the following table.

Pathology

(mode

dosing)

Hematologic indices

Recommendations

SM and HES / HAL, caused by anomalous FIPlLl-PDGFRa- tyrosine kinase (initial dose of imatinib 100 mg / day)

AChN <1 x 10⁹/ l and / or

ЧТ ** <50х 10⁹/ l

1. Interrupt imatinib therapy before ASC≥1,5 x10⁹/ l and Th≥75x 10⁹/ l

2. Resumption of treatment with the drug in a dose used before the occurrence of a serious adverse reaction

CML in

chronic

phase,

malignant GISO,

MDS / MPZ, CM and HES / HAL in adult patients (initial dose of 400 mg / eutin)

АЧН <1.0 х 10⁹/ l and / or

Th <50 x 10⁹/ l

1. Interrupt therapy with imatinib before ACN ≥1,5 x 10⁹/ l and Thurs ≥75 x 10⁹/ l

2. Resumption of treatment with the drug in a dose used before the occurrence of a serious adverse reaction

3. In the case of a repeated decrease in ACH <1 x 10⁹/ l and / or ЧТ <50 х 10 / l repeat step 1 and resume therapy with a reduced dose of 300 mg / day

CML in

chronic phase in children (dose 340 mg / m '/ day)

АЧН <1.0 х 10⁹/ l and / or

Th <50 x 10⁹/ l

1. Interrupt therapy with imatinib before ACN ≥1.5 x 10⁹/ L and TH ≥75 x 10⁹/ l

2. Resumption of treatment with the drug in a dose used before the occurrence of a serious adverse reaction

3. In case of a repeated decrease АЧН < 1.0 x 10⁹/ l and / or
Th <50 x 10⁹/ l repeat step 1 and resume therapy with a reduced dose of 260 mg / m / day

XMJI in the phase of acceleration or blastiogo crisis, PY-OLL (initial dose of 600 mg / day)

¹AFN <0.5 x 10⁹/ l and / or

Th <10 x 10⁹/ l

1. Make sure that cytopenia is caused by leukemia (aspiration or bone marrow biopsy)

2. If cytopenia is not associated with leukemia, lower the dose of imatinib to 400 mg / day

3. If cytopenia continues for 2 weeks, reduce the dose of imatinib to 300 mg / day

4. If cytopenia has been inactive for 4 weeks and is not associated with leukemia, interrupt treatment with imatinib before restoring ACN ≥1.0 x 10⁹/ L and TH≥20 х 10⁹/ l, then resume treatment at a dose of 300 mg / day.

CML in the phases of acceleration and blastic crisis in children

(initial dose of 340 mg / m / day)

¹АЧН <0,5х 10⁹/ l and / or

Th <10 x 10⁹/ l

1. Make sure that cytopenia is caused by leukemia (aspiration or bone marrow biopsy)

2. If cytopenia is not associated with leukemia, lower the dose of imatinib to 260 mg /m²/day

3. If cytopenia has been inactive for 2 weeks, reduce the dose of imatinib to 200 mg / m².

4. If cytopenia has been inactive for 4 weeks and is not associated with leukemia, interrupt treatment with imatinib before restoring AFC ≥1.0 x 10⁹/ l and Thurs ≥20 х 10⁹/ l. then resume treatment at a dose of 200 mg / m.

VDFS (dose

800 mg / day)

АЧН <1.0 х 10⁹/ l and / or

Th <50 x 10⁹/ l

1. Interrupt therapy with imatinib before ACN ≥1.5 x 10⁹/ L and TH ≥75 х 10⁹/ l

2. Resumption of treatment with the drug at a dose of 600 mg / day.

3. In the case of a repeated decrease in AFN <1 x 10⁹/ l and / or ЧТ <50 х 10⁹/ l repeat step 1 and resume therapy with a reduced dose of 400 mg / day

* AChN = absolute number of neutrophils ** ЧТ = number of platelets

¹ at least after 1 month of therapy

Use in special patient groups

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 used in a minimum daily dose of 400 mg. With the development of undesirable toxic effects, the dose should be reduced. Caution should be exercised when Imatinib medications are used in patients with severe hepatic insufficiency.

Classification of hepatic insufficiency

Lightweight

Total bilirubin = 1.5 VGN

ACT > VGN (mb in norm or <VGN if the general bilirubin> VGI)

Moderate

Total bilirubin> 1.5-3 VGN ACT: any value

Heavy

Total bilirubin> 3-10 VGN ACT: any value

ACT = aspartate aminotransferase

Patients with impaired renal function

Patients with impaired renal function and patients who require systematic hemodialysis, the drug is prescribed in a minimum initial dose of 400 mg per day. Care should be taken when using the drug in patients in this group. With intolerance, the dose should be reduced. With good tolerability and insufficient effectiveness of therapy, the dose of Imatinib can be increased.

Elderly patients

Correction of the dosing regimen in elderly patients is not required.

Side effects:

In the advanced stages of the disease, the causal relationship of adverse reactions to the therapy is difficult due to the development of multiple disorders in patients,associated with concomitant pathology, its progression and the use of various drugs.

In most patients Imatinib medak is characterized by good tolerability; the withdrawal of the drug due to the development of side effects was noted only in a small (not more than 5%) number of patients.

When using the drug for different indications, there were similar side effects. In patients with XMJI, myelosuppression is more likely to develop, which is probably related to the underlying disease, and patients with GISO have more frequent gastrointestinal and intrapulmonary hemorrhages.

The most frequent (≥10%) adverse events associated with taking the drug were mild nausea, vomiting, diarrhea, abdominal pain, fatigue, myalgia, muscle cramps, skin rash. Periorbital edema or edema of the lower extremities were often noted, but they were rarely expressed and stopped with diuretics, maintenance therapy, or with a decrease in imatinib dose.

When imatinib was used as part of high-dose chemotherapy in patients with Ph + OJIJI, transitory hepatic toxicity was noted, manifested by increased transaminase activity and hyperbilirubinemia.

Such side effects as pleural effusion, ascites, pulmonary edema, rapid weight gain, with the development of peripheral edema or in their absence, can generally be defined as manifestations of the "fluid retention" syndrome. They are usually stopped by interrupting therapy with imatinib, the appointment of diuretics and other necessary supportive activities. Nevertheless, in some cases, these phenomena can acquire the character of serious and even life-threatening complications; there were several deaths among patients with blast crisis, complicated by pleural effusion, congestive heart failure and kidney failure.

Adverse reactions observed in children did not have specific differences from those in adults.

The following are the side reactions observed with imatinib therapy, grouped by organs and systems, indicating the frequency of their occurrence according to the following gradation: very often (≥1/10), often (from ≥1 / 100 to <1/10), infrequently (from ≥1 / 1000 to <1/100), rarely (from ≥1 / 10000 to <1/1000), very rarely (<1/10000), the frequency is unknown (can not be determined from the available data).

Infectious and parasitic diseases: infrequent - herpes simplex, herpes zoster, rhinopharyngitis, 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 disintegration syndrome.

On the part of the hematopoiesis system: very often - neutropenia, thrombocytopenia, anemia; often - pancytopenia, febrile neutropenia; infrequently - thrombocythemia, lymphopenia, oppression of bone marrow function, eosinophilia, lymphadenopathy; rarely - hemolytic anemia.

Metabolic and nutritional disorders: often - anorexia; infrequently - hypokalemia, increase or decrease in appetite, hypophosphatemia, dehydration, gout, hyperuricemia, hypercalcemia, hyperglycemia, hyponatremia; rarely - hyperkalemia, hypomagnesemia.

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

Impaired nervous system: very often - headache², often - dizziness, paresthesia, a violation of taste, hypoesthesia; infrequently - migraine, drowsiness, loss of consciousness, peripheral neuropathy, memory impairment, sciatica, restless legs syndrome, tremor, hemorrhagic stroke; 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, scleral hemorrhage, retinal hemorrhage, blepharitis, macular edema; rarely - cataract, glaucoma, edema of the optic disc.

Hearing impairments and labyrinthine disturbances: infrequently - vertigo, noise in the ears, decrease (until loss) of hearing.

From the side of the cardiovascular system³: often - hot flashes, hemorrhages; infrequently - increased blood pressure, bruises, subdural hematomas, cold extremities, decreased blood pressure, Raynaud's syndrome, tachycardia, palpitations, congestive heart failure, pulmonary edema; rarely - arrhythmia, atrial fibrillation, sudden cardiac arrest, myocardial infarction, angina pectoris, pericardial effusion.

From the respiratory system, chest and mediastinum: often shortness of breath, nosebleeds, cough; infrequently - pleural effusion⁴, pain in the pharynx, larynx, pharyngitis; rarely - pleural pain, pulmonary fibrosis, pulmonary hypertension, pulmonary hemorrhage.

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

Disorders from the liver and bile ducts: often - increased activity of "liver" enzymes; infrequently - hyperbilirubinemia, hepatitis, jaundice; rarely - liver failure⁵, necrosis of the liver.

From the side of the rut and subcutaneous tissues: very often - periorbital edema, dermatitis, eczema, skin rash; often - itching, swelling of the face, dry skin, erythema, alopecia, night sweats,photosensitivity reaction; infrequent - pustular rash, bruises, sweating, urticaria, ecchymosis, increased tendency to hemorrhage, hypotrichosis, hypopigmentation / hyperpigmentation of the skin, exfoliative dermatitis, increased nail brittleness, folliculitis, petechiae, psoriasis, purpura, bullous rash; rarely - acute febrile neutrophilic dermatosis (Sweet syndrome), nail color change, angioedema, vesicular rash, erythema multiforma, leukocytoclastic vasculitis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis.

From the osteomuscular system and connective tissue: very often - muscle spasms and cramps, musculoskeletal pain, including myalgia, arthralgia, bone pain⁶, often - swelling of the joints; infrequent - stiffness of joints and muscles; rarely - muscle weakness, arthritis, myopathy / rhabdomyolysis.

From the side of the kidneys and urinary tract: infrequently - pain in the kidney, hematuria, acute renal failure, frequent urination.

Disorders from the reproductive and endocrine systems: infrequently - gynecomastia, erectile dysfunction, menorrhagia,violation of the menstrual cycle, sexual dysfunction, pain in the nipples, enlargement of the mammary glands, swelling of the scrotum; rarely - women bleed from the yellow body, bleeding from the ovarian cyst.

Other: very often - fluid retention and edema, increased fatigue, weight gain; often - weakness, fever, anasarca, chills, trembling, weight loss; infrequently - a pain in the chest, a feeling of malaise.

Influence on the results of laboratory studies: infrequently - an increase in the concentration of creatinine and the activity of creatine phosphokinase, lactate dehydrogenase, alkaline phosphatase in the blood; rarely - increased activity of amylase in the blood.

¹ Pneumonia was most frequently observed in patients with XML in the phase of acceleration, imperious crisis and with inoperable and / or metastatic malignant GIS.

² Headache is most common in patients with unresectable and / or metastatic malignant gastrointestinal stromal tumors. Side effects from the cardiovascular system, including congestive heart failure, were more frequent in patients with CML in the phase of acceleration and blast crisis compared with patients with XML inchronic phase.

³ Hemorrhages and hematomas were more often observed in patients with CML in the accelerated phase and with blast crisis.

⁴ Pleural effusion is more often noted in patients with CML in the phase of acceleration and blast crisis compared with patients with CML in the chronic phase.

⁵ Individual cases of hepatic insufficiency with lethal outcome and liver necrosis have been reported.

⁶ Musculoskeletal pain was more often observed in patients with CML.

The following undesirable reactions were observed in limited patient populations, mainly during the post-marketing period, including reports of adverse reactions, descriptions of individual clinical cases, clinical pharmacological data, observations of imatinib application outside of the recorded indications; in these cases, it is not possible to determine the incidence of these side effects and to confirm their occurrence in connection with imatinib use.

Benign, malignant and unspecified neoplasms (including cysts and polyps): intratumoral bleeding / tumor necrosis.

From the immune system: anaphylactic shock.

From the nervous system: cerebral edema.

From the side of the organ of vision: vitreous hemorrhage.

From the side of the cardiovascular system: thrombosis / embolism, pericarditis, cardiac tamponade.

From the respiratory system: acute respiratory failure, interstitial lung diseases.

From the digestive system: intestinal obstruction, intestinal perforation, diverticulitis.

From the skin and subcutaneous tissues: palmar-plantar syndrome, lichenoid keratosis, flat lichen, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms.

From the musculoskeletal system: avascular necrosis / necrosis of the head of the femur, growth retardation in children.

Cases of development of respiratory insufficiency with lethal outcome were reported in patients with a common disease, with severe infectious diseases, severe neutropenia and other serious concomitant diseases.

Influence on the results of laboratory studies

Hemogram

In patients with CML, cytopenia is usually observed, especially neutropenia and thrombocytopenia, with a higher frequency with the administration of the drug at high doses (≥750 mg, Phase I study data).The frequency of development of cytopenia clearly depended on the phase of the disease; frequency of neutropenia of the 3rd degree of severity (ACHN <1.0x10⁹/ l) and thrombocytopenia (Th <50 x 10⁹/ l) was 4-6 times higher with a power crisis and in the acceleration phase (59-64% and 44-63% for neutropenia and thrombocytopaedure, respectively) compared to the chronic phase of newly diagnosed CML (16.7% for neutropenia and 8.9% for thrombocytopenia).

In the chronic phase of newly diagnosed CML neutropenia of the 4th degree (ACH <0.5 x 10⁹/ л) and thrombocytopenia (ЧТ <10 х 10⁹/ l) were observed in 3.6% and less than 1% of patients, respectively. The median duration of episodes of neutropenia and thrombocytopenia usually ranged from 2 to 3 weeks and from 3 to 4 weeks, respectively. The reactions under consideration were usually stopped by reducing the dose or interrupting the treatment with imatinib; in rare cases it was necessary to cancel treatment. In children with CML, the most frequent manifestation of toxicity was grade 3-4 cytopenia, which included neutropenia, thrombocytopenia, and anemia, and manifested itself usually during the first few months of treatment.

Biochemical assays

Increased activity of traasaminases (less than 5% of cases) or concentrationbilirubin (less than 1% of cases) was noted in patients with CML and was usually controlled by a decrease in imatinib dose or a temporary interruption of therapy (median duration of episodes was about 1 week). The abolition of therapy in connection with the change in laboratory parameters of liver function in patients with CML was performed in less than 1% of cases.

There are some reports of the development of cytolytic and cholestatic hepatitis, as well as liver failure, in some cases leading to death; in one of the cases the patient took high doses of paracetamol.

Overdose:

Single cases of imatinib overdose are known.

In case of an overdose, medical supervision and symptomatic therapy are recommended. Usually the outcome of an overdose is favorable, there was an improvement in the condition of the patients or complete disappearance of the symptoms. The following describes the symptoms of an overdose with different doses of the drug.

Overdose in adult patients

When taking imatinib in a dose of 1200 - 1600 mg for 1-10 days: nausea, vomiting, diarrhea, skin rash, erythema, swelling, mostly swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite.

When imatinib was taken in a dose of 1800-3200 mg (the highest dose was 3200 mg per day for 6 days): general weakness, myalgia, gastrointestinal pain, increased activity of creatine phosphokinase and serum bilirubin concentration. In the literature, one case of imatinib administered to a patient once in a dose of 6400 mg was described: the patient developed nausea, vomiting, abdominal pain, fever, facial edema, neutropenia and increased transaminase activity.

With a random single dose of imatinib in a dose of 8 - 10 g, vomiting and gastrointestinal pain developed.

Overdose in children

After taking imatinib once in a dose of 400 mg, a 3-year-old boy developed vomiting, diarrhea, and anorexia. Another boy aged 3 years after taking imatinib once in a dose of 980 mg observed leukopenia and diarrhea.

Interaction:

Drugs that increase the concentration of imatinib in the blood plasma

With the simultaneous use of imatinib with drugs that inhibit the cytochrome P450 isoenzyme CYP3A4 (for example, ketoconazole, itraconazole, erythromycin, clarithromycin, posaconazole, voriconazole, telithromycin, protease inhibitors (indinavir, lappnavir, ritonavir, saquinavir, teltopresvir, nelfinavir, boceprevir)) may increase the concentration of imatinib in the blood plasma due to a slowing of the metabolism of imatinib. In healthy volunteers, a single application of cystoconazole together with imatinib caused an increase in Cmax and AUC of imatinib by 26% and 40%, respectively.

Care should be taken when prescribing imatinib with CYP3A4 isoenzyme inhibitors.

Drugs that reduce the concentration of imatinib in the blood plasma

Simultaneous use of imatinib with drugs that are inducers of CYP3A4 (for example, dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital, fosphenytoin, primidone or drugs based on St. John's wort) can lead to a significant acceleration of imatinib metabolism, a decrease in its concentration in the blood plasma, and , as a result, a decrease in the effectiveness of the therapy. Repeated administration of rifampicin 600 mg reduces Cmax and AUC imatinib after its single dose of 400 mg at a value of at least 54% and 74%, respectively, compared with similar values for imatinib without previous administration of rifampicin.In patients with malignant gliomas receiving imatinib therapy, the combined use of antiepileptic drugs that are inducers of the CYP3A4 enzyme (such as carbamazepine, oxcarbazepine, phenytoin), leads to a decrease in the AUC imatinib by approximately 73%.

Joint imatinib with rifampicion and other powerful inducers of CYP3A4 should be avoided.

Drugs, the concentration of which in the plasma can change under the effect of imatinib

With the simultaneous use of imatinib and simvastatin, there is an increase in Cmax and AUC of simvastatin (which is the substrate of CYP3A4) in the blood, on average, by 2 and 3.5 times, respectively, which is a consequence of the inhibition of CYP3A4 by imatinib. Therefore, caution should be exercised when prescribing imatinib together with drugs that are substrates of CYP3A4 and have a narrow range of therapeutic concentrations (eg, cyclosporine, pimozide, tacrolimus, sirolimus, ergotamine, fentanyl, terfenadine, bortezomib, docetaxel, quinidine). Imatinib can increase the concentration in the plasma of drugs,metabolized with the participation of CYP3A4 (such as triazolo-benzodiazepines, dihydropyridinium calcium channel blockers, some inhibitors of HMG-CoA reductase, including statins).

Because warfarin metabolism occurs with the participation of CYP2C9, patients who need anticoagulant therapy should be given low-molecular or standard heparins.

Imatinib in vitro inhibits the activity of the cytochrome P450 isoenzyme CYP2D6 at the same concentrations that inhibit the activity of CYP3A4. When imatinib is administered twice a day at a dose of 400 mg, DP1ax and AUC metoprolol, the metabolism of which occurs with the participation of CYP2D6, increases by approximately 23%. The use of drugs that are substrates of CYP2D6 and having a narrow range of therapeutic concentrations, together with imatinib, does not require dose adjustment, but caution is necessary in such cases. Patients receiving mstoprolol and imatinib, clinical observation should be provided.

Imatinib inhibits O-glucuronidation of paracetamol in vitro. This effect was not observed in vivo after imatinib at a dose of 400 mg and paracetamol at a dose of 1000 mg. The interaction of these drugs in large doses has not been studied.Therefore, with the joint use of imatinib with paracetamol, care should be taken.

In patients undergoing thyroidectomy, the consistent use of imatinib and levothyroxine sodium can cause a decrease in the concentration of the latter in the blood plasma, which requires precautions when prescribing drugs in this combination. The mechanism of this interaction is currently unknown. Despite the clinical experience gained so far with imatinib as part of complex chemotherapy, the interaction of imatinib with other components has not been studied in detail. In particular, such side effects of imatinib, such as hepatoxicity, myelosuppression, etc., may increase. So, it was reported on the increase in hepatotoxicity of imatinib when it is combined with L-asparaginase. Therefore, when using imatinib as part of complex chemotherapy, special care must be taken.

Special instructions:

Treatment with Imatinib medication should be conducted by a doctor who has experience of antitumor therapy.

When handling the product, especially for women of childbearing age, you must be careful: do not inhale the contents of the capsules and contact with skin and eyes. If it is necessary to open the capsules, immediately after this procedure, you should thoroughly wash your hands.

The combined application of imatinib with other drugs there is a risk of drug interactions. In this regard care must be taken when used in conjunction with imatinib ketoconazole and other active CYP3A4 isozyme inhibitors, drugs that are CYP3A4 substrates and having a narrow range of therapeutic concentrations (such as ciclosporin, Pimozide) and CYP2C9 substrates with a narrow therapeutic range of concentrations (warfarin and other coumarin derivatives).

Combined use of imatinib with drugs which are inducers of CYP3A4 (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, phenobarbital, on the basis of Hypericum perforatum drugs) may lead to a decrease of its concentration in blood plasma and, as a result, reduce the effectiveness of the therapy.Combined use of imatinib with CYP3A4 inducers should be avoided.

There have been reports of cases of hypothyroidism in the use of imatinib in patients who undergone thyroidectomy and are receiving substitution treatment with levothyroxine sodium, therefore, when imatinib is used in such patients, the level of thyroid-stimulating hormone in the blood plasma must be regularly monitored. Imatinib metabolized mainly in the liver; when using the drug in patients with impaired liver function (even insignificant), it is necessary to regularly conduct clinical analyzes of peripheral blood and monitor liver function (hepatic granaminase activity, alkaline phosphatase and bilirubin concentration in blood serum).

There have been reports of severe violations of liver function and liver necrosis when imatinib is used. When imatinib was used in high-dose combined chemotherapy regimens, there was an increase in hepatic toxicity. With a combination of imatinib and chemotherapy regimens that can potentially cause liver dysfunction, liver function should be carefully monitored.Due to the fact that with the use of Imatinib, severe fluid retention (pleural effusion, peripheral edema, pulmonary edema, ascites) is recommended, it is recommended to regularly monitor the body weight of patients. In the case of an unexpected rapid increase in body weight, the patient should be examined and, if necessary, to take adequate measures, including symptomatic therapy. The highest frequency of fluid retention is observed in elderly patients with concomitant cardiovascular diseases. Care should be taken when using imatinib in patients with cardiovascular disease. Patients with cardiovascular diseases, an increased risk of cardiac or renal insufficiency, or an indication of them in a history should be provided with a thorough clinical observation and, if necessary, timely treatment. In patients with HES with concomitant cardiovascular disease, at the beginning of therapy with imatinib, there were isolated cases of development of cardiogenic shock / left ventricular failure. These undesirable phenomena are stopped after the introduction of systemic glucocorticosteroids, taking measures,aimed at maintaining blood circulation, and temporary withdrawal imatinib. When imatinib is prescribed to patients with HES / HAL, the ratio of expected benefit to potential risk should be assessed.

Myelodysplastic / myeloproliferative diseases (MDD / MPD) can be associated with a high level of eosinophils. In patients with MDD / MPD associated with a high level of eosinophils, as in patients with HES / HAL, an ECG test should be performed before the imatinib is used and the serum concentration of cardiospecific troponin should be determined and the cardiologist should be consulted. 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 and ensure the observation of a cardiologist.

Due to the risk of development of tumor lysis syndrome, imatinib should be corrected, if necessary, for clinically pronounced dehydration and elevated levels of uric acid.

In patients with GISD, gastrointestinal bleeding can occur both in the abdominal organs and in the liver, depending on the location of the tumor sites.It is necessary to monitor the state of the gastrointestinal tract in patients with metastatic malignant GISD when starting therapy with imatinib.

During therapy with imatinib and at least 3 months after it is completed, reliable methods of contraception should be used.

Laboratory research

During treatment with imatinib, a thorough clinical blood test should be performed regularly. In patients with XML, the probability of neutropenia and thrombopenia is higher in the phase of acceleration and blast crisis than in the chronic phase. It is necessary to carry out regular monitoring of liver function (activity of "liver" transaminases, alkaline phosphatase, serum bilirubin concentration).

In patients with impaired renal function, an increase in the concentration of imatinib in the blood may be possible, treatment of such patients should begin with a minimum effective starting dose. Care should be taken when treating patients with severe renal dysfunction. If imatinib is poorly tolerated, its dose should be reduced.

Imatinib use in children

Growth in children and adolescents who were taking imatinib. Long-term effects of imatinib on growth have not been studied to date; in patients in this group, careful monitoring of growth dynamics is recommended.

Fertility

Special studies of the effect of the drug on fertility in humans have not been conducted. Women and men of childbearing age before starting treatment with imatinib should consult with a doctor.

Effect on the ability to drive transp. cf. and fur:Patients should be warned about the possibility of developing dizziness, vision disorders, drowsiness during therapy with imatinib. If the above undesirable phenomena occur, you should refrain from driving the car and controlling the mechanisms.

Form release / dosage:Capsules 100 mg and 400 mg.

Packaging:

Dosage of 100 mg: 15 capsules in a blister polyamide / aluminum / PVC / / aluminium. For 4 blisters together with instructions for use in a cardboard bundle.

Dosage of 400 mg: 10 capsules in a polyamide / aluminum / PVC blister // aluminum. For 3 blisters together with instructions for use in a cardboard bundle.

Storage conditions:At a temperature of no higher than 25 ° C. Keep out of the reach of children.

Shelf life:

3 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LP-003010

Date of registration:01.06.2015 / 02.02.2016

Expiration Date:01.06.2020

The owner of the registration certificate:medac GmbHmedac GmbH Germany

Manufacturer: & nbsp

PABIANICE PHARMACEUTICAL WORKS POLFA Poland

Representation: & nbspTIRUFARM, LLCTIRUFARM, LLCRussia

Information update date: & nbsp09.11.2017

Illustrated instructions

Instructions

Imatinib Medak (Imatinib medak)