IMATINIB 400 mg. No. 30 in stock

Side effects:

Central and peripheral nervous system: dizziness, headache, insomnia, fainting, hemorrhagic stroke, peripheral neuropathy, drowsiness, migraine, depression, cognitive impairment, confusion, cerebral edema, convulsions.

Respiratory system: shortness of breath, cough, rarely - pneumonitis, respiratory failure, dysphonia, pulmonary edema.

Hematopoietic system: anemia, neutropenia, thrombocytopenia, leukopenia, febrile neutropenia, rarely - lymphopenia, coagulopathy.

Cardiovascular system: decreased blood pressure, ventricular dysfunction, myocardial infarction, supraventricular arrhythmia, thrombosis, rarely - angina pectoris, myocardial ischemia, cardiomyopathy, atrial fibrillation, hypovolemic shock, pulmonary embolism, vasculitis, bleeding.

Digestive system: stomatitis/mucositis, abdominal pain, vomiting, diarrhea, constipation, nausea, gastroesophageal reflux disease, esophagitis, colitis, intestinal obstruction, impaired gastric emptying, rarely - dysphagia, gastrointestinal bleeding, gastritis.

Musculoskeletal system: myalgia, arthralgia, muscle weakness, rarely - muscle spasms, trismus.

Dermatological reactions: alopecia, skin rashes, erythrodysesthesia syndrome of fingers and toes, skin hyperpigmentation, itching, skin peeling, nail damage, rarely - erythema multiforme.

Sense organs: conjunctivitis, blurred vision, lacrimation, tinnitus.

Reproductive system: breast enlargement, gynecomastia, nipple pain, scrotal swelling, decreased potency.

Allergic reactions.

Imatinib caps 100 mg No. 120

Compound

Active substance: imatinib 100 mg. Excipients: microcrystalline cellulose - 48.5 mg, povidone K-25 - 3.7 mg, crospovidone - 5 mg, colloidal silicon dioxide - 1.5 mg, magnesium stearate - 1.8 mg.

Pharmacokinetics

After oral administration, bioavailability is on average 98%. The coefficient of variation for AUC is 40-60%. When taken with a high-fat meal, compared to taking on an empty stomach, there is a slight decrease in the degree of absorption (decrease in Cmax by 11%, AUC by 7.4%) and a slower rate of absorption (extension of Tmax by 1.5 hours).

At clinically significant concentrations of imatinib, its binding to plasma proteins is about 95% (mainly to albumin and acid alpha glycoprotein, to a minor extent to lipoprotein).

The main metabolite of imatinib circulating in the bloodstream is an N-demethylated piperazine derivative, which in vitro has pharmacological activity similar to that of the unchanged active substance. The AUC value for the metabolite is 16% of the AUC of imatinib.

After oral administration of 14C-labeled imatinib, 68% of the administered dose was excreted in feces and 13% of the dose in urine over 7 days. About 25% of the dose is excreted unchanged (20% in feces and 5% in urine). The remaining amount of imatinib is excreted as metabolites.

T1/2 of imatinib in healthy volunteers was about 18 hours.

If liver function is impaired, the concentration of imatinib in the blood plasma may increase.

Indications for use

newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in children and adults;
Ph+ CML in the chronic phase with failure of previous interferon alpha therapy or in the acceleration phase, or blast crisis in children and adults;
newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in children and adult patients in combination with chemotherapy;
relapsed or refractory Ph+ ALL in adult patients as monotherapy;
myelodysplastic/myeloproliferative diseases associated with gene rearrangements of the platelet growth factor receptor in adult patients;
systemic mastocytosis in adult patients with no D816V c-Kit mutation or with unknown c-Kit mutation status;
hypereosinophilic syndrome and/or chronic eosinophilic leukemia in adult patients with positive or negative abnormal FIP1L1-PDGRF alpha-tyrosine kinase;
unresectable and/or metastatic malignant gastrointestinal stromal tumors (GISTs) positive for c-Kit (CD117) in adult patients;
adjuvant therapy in adult patients with c-Kit (CD117)-positive GISTs;
inoperable, recurrent and/or metastatic dermatofibrosarcoma protuberans in adult patients.

Contraindications

hypersensitivity to imatinib;
pregnancy;
breastfeeding period;
children's age (efficacy and safety have not been established) up to 1 year 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.

Carefully:

patients with severe liver failure;
patients with severe renal impairment;
patients with diseases of the cardiovascular system or with risk factors for developing heart failure;
during regular hemodialysis procedures;
when used simultaneously with drugs that inhibit the CYP3A4 isoenzyme, strong inducers of the CYP3A4 isoenzyme. drugs that are substrates of the CYP3A4 isoenzyme;
when used simultaneously with paracetamol, warfarin.

Directions for use and doses

Inside. The dose, regimen and duration of treatment are determined individually, depending on the indications and age of the patient.

Storage conditions

In a place protected from light, at a temperature not exceeding 25 ° C.
Keep out of the reach of children.

Best before date

3 years. Do not use the drug after the expiration date.

special instructions

Treatment with imatinib should only be carried out under the supervision of a physician experienced in working with anticancer drugs.
Cases of severe fluid retention have been reported when using imatinib; regular monitoring of body weight is recommended. If unexpected rapid weight gain occurs, an evaluation should be performed and, if necessary, imatinib therapy should be temporarily discontinued and/or diuretics should be initiated.
When using imatinib, the development of neutropenia or thrombocytopenia was observed; These events had a clear relationship with the stage of the disease, and their incidence was higher in patients with CML in the blast crisis or accelerated phase compared with patients with CML in the chronic phase. It may be necessary to temporarily interrupt therapy or reduce the dose of imatinib.
When using imatinib, it is recommended to regularly conduct clinical blood tests and monitor liver function (transaminases, bilirubin, alkaline phosphatase). When used in patients with liver disease, a clinical blood test should be performed regularly and the activity of liver enzymes should be determined.
Imatinib and its metabolites are excreted by the kidneys to a small extent. Creatinine clearance decreases with age, and age does not have a significant effect on the pharmacokinetic parameters of imatinib. There was no correlation between imatinib exposure and the degree of renal impairment in patients with mild (creatinine clearance 40-59 ml/min) to severe (creatinine clearance <20 ml/min) renal impairment. However, if patients in this category are intolerant, the initial dose of imatinib should be reduced.
There are reports of the development of hypothyroidism during the use of imatinib in patients who have undergone thyroidectomy and are receiving replacement therapy with levothyroxine sodium. The concentration of thyroid-stimulating hormone in this category of patients should be regularly determined.
Careful monitoring of patients with cardiovascular diseases, risk factors for heart failure, and patients with a history of renal failure should be ensured. If signs or symptoms suggestive of these conditions are identified, the patient should be assessed and appropriate treatment initiated.
In patients with myelodysplastic/myeloproliferative diseases and high eosinophil counts, ECG and serum cardiac-specific troponin concentrations should be determined. If abnormalities are detected at the beginning of therapy, the possibility of prophylactic use of systemic corticosteroids for 1-2 weeks simultaneously with imatinib should be considered.
There are isolated case reports of gastric antrum vascular ectasia (GAVE syndrome), a rare cause of gastrointestinal bleeding, in patients with CML and ALL and other diseases.
It is necessary to monitor the gastrointestinal tract in patients with metastatic malignant GISTs (abdominal pain, gastrointestinal bleeding, constipation, etc.) at the beginning and throughout imatinib therapy. If necessary, consider discontinuing imatinib therapy.
Due to the risk of developing tumor lysis syndrome, clinically significant dehydration and increased uric acid concentrations should be corrected if necessary before using imatinib.
In patients who are carriers of the hepatitis B virus, reactivation of this virus is possible after treatment with BCR-ABL tyrosine kinase inhibitor drugs, such as imatinib. In some cases, when using drugs of this class, the development of acute liver failure or fulminant hepatitis has been observed, leading to liver transplantation or death.
Before initiating imatinib therapy, all patients should be screened for the presence of hepatitis B virus. A patient who is a carrier of hepatitis B virus and requires treatment with imatinib should be closely monitored for the development of signs and symptoms of an active infectious process both during and after imatinib therapy. months after its completion.

Description

Antitumor drug. Protein tyrosine kinase inhibitor.

Dosage form

Hard gelatin capsules, No. 2, the body and cap are opaque, white, the contents of the capsules are a mixture of granules and powder, white or white with a brown or yellow tint; It is allowed to compact the contents of capsules into capsule-shaped lumps that are easily broken when pressed.

Use in children

Imatinib is contraindicated for use under 1 year of age in patients with Ph+ acute lymphoblastic leukemia; up to 2 years in patients with Ph+ chronic myeloid leukemia; up to 18 years of age for other indications.

Action

Protein tyrosine kinase inhibitor. Inhibits the enzyme Bcr-Abl-tyrosine kinase at the cellular level, in vitro and in vivo. Selectively suppresses the proliferation and causes apoptosis of cell lines positive for Bcr-Abl, as well as young leukemic cells in chronic myeloid leukemia with a positive Philadelphia chromosome and in acute lymphoblastic leukemia.

In colony transformation studies performed on peripheral blood and bone marrow samples, imatinib was shown to selectively inhibit Bcr-Abl-positive colonies obtained from patients with chronic myeloid leukemia.

Imatinib has been shown to have antitumor activity when used as monotherapy in in vivo animal models using Bcr-Abl-positive tumor cells.

In addition, imatinib is an inhibitor of tyrosine kinase receptors for platelet-derived growth factor and stem cell factor, and also suppresses cellular responses mediated by the above factors.

In vitro, imatinib inhibits proliferation and induces apoptosis of gastrointestinal stromal tumor cells expressing kit mutations.

Side effects

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

From the hematopoietic system: very often - neutropenia, thrombocytopenia, anemia; often - pancytopenia, febrile neutropenia; uncommon - thrombocythemia, lymphopenia, suppression of bone marrow hematopoiesis, eosinophilia, lymphadenopathy; rarely - hemolytic anemia

Metabolism: very often - weight gain; often - anorexia, weight loss; uncommon - hypokalemia, increased appetite, hypophosphatemia, decreased appetite, dehydration, hyperuricemia, gout, hypercalcemia, hyperglycemia, hyponatremia; rarely - hyperkalemia, hypomagnesemia.

From the mental side: often - insomnia; infrequently - depression, decreased libido, anxiety; rarely - confusion.

From the nervous system: very often - headache; often - dizziness, paresthesia, taste disturbance, hypoesthesia; uncommon - migraine, somnolence, fainting, peripheral neuropathy, memory impairment, sciatica, restless legs syndrome, tremor, hemorrhagic stroke; rarely - increased intracranial pressure, convulsions, optic neuritis.

From the organ of vision: often - swelling of the eyelids, increased lacrimation, conjunctival hemorrhages, conjunctivitis, dry eye syndrome, blurred vision; uncommon - eye irritation, eye pain, orbital edema, scleral hemorrhage, retinal hemorrhage, blepharitis, macular edema; rarely - cataracts, papilledema, glaucoma.

Auditory and vestibular disorders: uncommon - vertigo, tinnitus, hearing loss.

From the cardiovascular system: often - hot flashes, hemorrhages; uncommon - palpitations, tachycardia, chronic heart failure, pulmonary edema, increased or decreased blood pressure, hematoma, subdural hematoma, cold extremities, Raynaud's syndrome; rarely - arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina pectoris, pericardial effusion.

From the respiratory system: often - nosebleeds, shortness of breath, cough; uncommon - pleural effusion, pain in the pharynx or larynx, pharyngitis; rarely - pleural pain, pulmonary fibrosis, pulmonary hypertension, pulmonary hemorrhage.

From the digestive system: very often - nausea, vomiting, diarrhea, dyspepsia, abdominal pain; often - bloating, flatulence, constipation, gastroesophageal reflux, dry mouth, gastritis; uncommon - stomatitis, ulceration of the oral mucosa, gastrointestinal bleeding, belching, melena, esophagitis, ascites, gastric ulcer, hematemesis, cheilitis, dysphagia, pancreatitis; rarely - colitis, paralytic/obstructive intestinal obstruction, inflammation of the colon.

From the liver and biliary tract: often - increased activity of liver transaminases; uncommon - jaundice, hepatitis, hyperbilirubinemia; rarely - liver failure, liver necrosis.

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

From the musculoskeletal system: very often - muscle spasms and cramps, musculoskeletal pain, including myalgia and arthralgia, bone pain; often - swelling of the joints; infrequently - stiffness of muscles and joints; rarely - muscle weakness, arthritis.

From the urinary system: uncommon - kidney pain, hematuria, acute renal failure, frequent urination.

From the reproductive system: uncommon - gynecomastia, erectile dysfunction, menorrhagia, menstrual irregularities, sexual dysfunction, nipple pain, breast enlargement, scrotal swelling.

From the body as a whole: very often - fluid retention, swelling, increased fatigue; often - weakness, fever, anasarca, chills, trembling; infrequently - chest pain, general malaise.

From laboratory parameters: infrequently - increased concentration of creatinine in the blood, increased activity of CPK in the blood, increased activity of alkaline phosphatase, LDH; rarely - increased amylase activity in blood plasma.

Use during pregnancy and breastfeeding

Contraindicated for use during pregnancy and lactation (breastfeeding).

Interaction

When imanitib is used simultaneously with drugs that inhibit the cytochrome P450 isoenzyme CYP3A4, for example, viral protease inhibitors (indinavir, lopinavir, ritonavir, saquinavir, telaprevir, nelfinavir, boceprevir), azole antifungals (including ketoconazole, itraconazole, posaconazole, voriconazole), some macrolide antibiotics (erythromycin, clarithromycin, telithromycin), the metabolism of imatinib may slow down and its concentration in the blood plasma may increase. Caution is required when using imatinib concomitantly with drugs that are inhibitors of CYP3A4 isoenzymes.
The simultaneous use of drugs that are inducers of the CYP3A4 isoenzyme (for example, rifampicin, dexamethasone, St. John's wort preparations, antiepileptic drugs: carbamazepine, oxcarbazepine, phenytoin, primidone) can lead to increased metabolism of imatinib and, as a result, a decrease in its concentration in the blood plasma and ineffectiveness therapy. The simultaneous use of imatinib and strong inducers of the CYP3A4 isoenzyme should be avoided.
With simultaneous use of imatinib and simvastatin, there is an increase in Cmax and AUC of simvastatin by 2 and 3.5 times, respectively, which is a consequence of inhibition of CYP3A4 by imatinib. Caution is recommended during concomitant use of imatinib and drugs that are CYP3A4 substrates and have a narrow therapeutic concentration range (for example, cyclosporine, pimozide, tacrolimus, sirolimus, ergotamine, fentanyl, terfenadine, bortezomib, docetaxel, quinidine). Imatinib may increase the serum concentrations of other drugs metabolized by the CYP3A4 isoenzyme (triazolobenzodopazepines, dihydropyridine, slow calcium channel blockers, most HMG-CoA reductase inhibitors, including statins).
Imatinib also inhibits CYP2C9 and CYP2C19 in vitro. When used simultaneously with warfarin, an increase in prothrombin time was observed. When used simultaneously with coumarin derivatives, short-term monitoring of prothrombin time is necessary at the beginning and end of therapy, as well as when changing the dosage regimen. Low molecular weight heparins should be considered as an alternative to warfarin.
The issue of drug interactions between imatinib and chemotherapy drugs in patients with Ph+ ALL has not been sufficiently studied. Caution must be exercised when using imatinib and chemotherapy drugs simultaneously due to a possible increase in the risk of drug complications, such as hepatotoxicity, myelosuppression and others.
When imatinib is combined with chemotherapy drugs in high doses, transient liver toxicity may develop in the form of an increase in the activity of liver transaminases and hyperbilirubinemia. Monitoring of liver function should be considered when imatinib is combined with chemotherapy regimens that have the potential to cause liver dysfunction.
In vitro, imatinib inhibits the cytochrome P450 isoenzyme CYP2D6 at the same concentrations at which it inhibits the CYP3A4 isoenzyme.
In patients after thyroidectomy receiving hormone replacement therapy with levothyroxine sodium, its concentration may be reduced when used simultaneously with imatinib.
There have been reports of the development of liver damage with simultaneous use of imatinib and asparaginase.
Cases of fatal liver failure have been reported when imatinib was taken concomitantly with paracetamol.

Overdose

Overdose in adults

When taking imatinib at a dose of 1200-1600 mg for 1-10 days, a patient with chronic myeloid leukemia in the blast crisis phase experienced nausea, vomiting, diarrhea, skin rash, erythema, edema, swelling mainly of the face, fatigue, muscle spasms, thrombocytopenia , pancytopenia, abdominal pain, headache, decreased appetite.

When taking imatinib at a dose of 1800-3200 mg (the highest dose was 3200 mg per day for 6 days), weakness, myalgia, gastrointestinal pain, increased creatine phosphokinase activity and bilirubin concentration in the blood plasma were observed. When using imatinib at a dose of 6400 mg once, the patient developed nausea, vomiting, abdominal pain, hyperthermia, facial swelling, a decrease in the number of neutrophils and an increase in the activity of “liver” transaminases in the blood serum.

When taking imatinib at a dose of 8-10 g, vomiting and gastrointestinal pain were observed once.

Overdose in children and adolescents

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

Treatment: in case of overdose, symptomatic therapy is carried out. There is no known antidote to imatinib.

Impact on the ability to drive vehicles and operate machinery

Some side effects, such as dizziness and blurred vision, may adversely affect the ability to drive vehicles and perform other potentially hazardous activities that require increased concentration and psychomotor speed. In this regard, patients who experience the described adverse events should refrain from performing these types of activities.

Special instructions:

Individuals of reproductive age are advised to use reliable methods of contraception while taking imatinib and for 3 months after treatment.

Patients receiving treatment with imatinib are prohibited from driving or operating moving machinery.

There are contraindications. Consult your doctor.

You can buy Imatinib 400 mg No. 30 the EUROPHARM Pharmacy

Get more information and order Imatinib 400 mg. No. 30 by phone 8 (495) 120-06-11

pharmachologic effect

Pharmacodynamics. Imatinib has a selective inhibitory effect on the Bcr-Abl tyrosine kinase enzyme, which is formed by the fusion of the Bcr gene (breakpoint cluster region) and the Abl proto-oncogene (Abelson); at the cellular level, it selectively suppresses proliferation and causes apoptosis of cell lines expressing Bcr-Abl tyrosine kinase, including immature leukemia cells produced in patients with Philadelphia chromosome-positive chronic myeloid leukemia (XMJI) and acute lymphoblastic leukemia (ALL). Selectively inhibits Bcr-Abl-positive colonies obtained from blood cells of CML patients. Inhibits proliferation and induces apoptosis of gastrointestinal tract (GIT) stromal tumor cells expressing tyrosine kinase with a c-Kit receptor mutation. Activation of receptors for platelet growth factors or the Abl fragment of tyrosine kinase can cause the development of both myelodysplastic/myeloproliferative diseases (MDS/MPD), hypereosinophilic syndrome, chronic eosinophilic leukemia and dermatofibrosarcoma protuberans. Activation of c-Kit receptor tyrosine kinase and platelet-derived growth factor receptors may underlie the pathogenesis of systemic mastocytosis. Imatinib inhibits cell signaling and cell proliferation resulting from dysregulation of the activity of platelet-derived growth factors and stem cell c-Kit receptor and Abl fragment tyrosine kinase. When using imatiib in patients with unresectable and/or metastatic malignant gastrointestinal stromal tumors, there was a significant increase in overall patient survival (48.8 months) and disease-free survival (21 months). Adjuvant drug therapy for gastrointestinal stromal tumors for 1 year reduces the risk of relapse by 89% and increases disease-free survival (38 months imatinib versus 20 months placebo). Adjuvant therapy for gastrointestinal stromal tumors for 3 years results in significantly longer overall survival and progression-free survival compared with therapy for 1 year. Pharmacokinetics. The pharmacokinetic parameters of imatinib were evaluated over a dose range from 25 mg to 1000 mg. Pharmacokinetic profiles were analyzed on day 1 and at steady-state imatinib plasma concentrations on days 7 or 28. Absorption. After oral administration, the bioavailability of the drug averages 98%. The coefficient of variation for the 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 was observed. When taking the drug with a high-fat meal, compared to taking it 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 11%, AUC by 7.4%) and a slower rate of absorption (an increase in the time to reach the maximum concentration of imatinib in blood plasma for 1.5 hours). About 95% of imatinib is bound to plasma proteins (mainly to albumin and acid alpha glycoproteins, to a small extent to lipoproteins). Imatinib is metabolized primarily in the liver to form the main metabolite (N-demethylated piperazine derivative), which circulates in the bloodstream. In vitro, the imatinib metabolite has pharmacological activity similar to that of the parent substance. The AUC value of the metabolite is 16% of the AUC of imatinib. The binding of the metabolite to plasma proteins is similar to that of imatinib. Excretion. After taking one dose, the drug is excreted from the body within 7 days, mainly in the form of metabolites (68% by the intestines and 13% by the kidneys). About 25% of the dose is excreted unchanged (20% by the intestines and 5% by the kidneys). The half-life of imatinib is approximately 18 hours. With repeated doses of the drug once a day, the pharmacokinetic parameters do not change, and the equilibrium concentration of imatinib exceeds the initial one by 1.5-2.5 times. In patients over 65 years of age, the volume of distribution increases slightly (by 12%). For patients weighing 50 kg, the average clearance of imatinib is 8.5 l/hour, and for patients weighing 100 kg - 11.8 l/hour. However, these differences are not significant and do not require adjustment of the drug dosage depending on the patient’s body weight. The pharmacokinetics of imatinib are independent of gender. Changes in clearance and volume of distribution of imatinib when used simultaneously with other drugs are insignificant and do not require dose changes. As in adult patients, the drug is rapidly absorbed when taken orally in children and adolescents under 18 years of age. The AUC in this group of patients in the 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 AUQ(0-24) values in children and adolescents on the first and eighth days after repeated dosing of the drug at 340 mg/m2 once a day, an increase in the value of this indicator by 1.7 times is noted, which indicates the accumulation of imatinib. Based on a pooled population pharmacokinetic analysis in children with hematological diseases, it was shown that imatinib clearance is directly proportional to body surface area; other demographic indicators (age, body weight and body mass index) do not have a clinically significant effect on imatinib exposure. Patients with hepatic impairment: In patients with varying degrees of hepatic impairment, mean AUC values do not increase. When using imatinib in patients with mild to moderate renal impairment (creatinine clearance >30 ml/min), there is an increase in drug exposure in plasma by 1.5-2.0 times, corresponding to an increase in the concentration of acidic alpha glycoproteins (special plasma proteins that bind to imaptipib). Because the drug is negligibly excreted by the kidneys, the clearance of free imatinib is similar in healthy volunteers and patients with impaired renal function. There is no correlation between drug exposure and the severity of renal impairment.

Interaction

In all cases when it becomes necessary to take imatinib simultaneously with any other drugs, you should consult your doctor. Drugs that are inhibitors of the cytochrome P450 isoenzyme CYP3A4 (protease inhibitors (indinavir, lopinavir, ritonavir, saquinavir, telaprevir, nelfinavir, boceprevir), posaconazole, voriconazole, ketoconazole, itraconazole, erythromycin, clarithromycin, telithromycin, etc.) may increase the concentration of imatinib in plasma as a result of a slowdown in its metabolism. Therefore, caution is required when used simultaneously with inhibitors of the CYP3A4 isoenzyme. Drugs that are inducers of the CYP3A4 isoenzyme (dexamethasone, phenytoin, carbamazepine, oxcarbamazepine, rifampicin, phenobarbital, fosphenytoin, primidone, preparations from St. John's wort) may reduce the concentration of imatinib in the blood plasma as a result of accelerating its metabolism and, as a result, lead to ineffectiveness of therapy . The simultaneous use of imatinib and strong inducers of the CYP3A4 isoenzyme should be avoided. In turn, imatinib can increase the plasma concentration of CYP3A4 isoenzyme substrates (cyclosporine, pimozide, most HMG-CoA reductase inhibitors, including simvastatin and other statins, triazolobenzodiazepines, dihydropyridine, blockers of “slow” calcium channels, substrates with a narrow therapeutic concentration range (tacrolimus, sirolimus, ergotamine, fentanyl, terfenadine, bortezomib, docetaxel, quinidine)). When used simultaneously with simvastatin, there is an increase in Cmax and AUC of simvastatin by 2 and 3.5 times, respectively. Therefore, caution should be exercised when imatinib is used concomitantly with these drugs. Imatinib inhibits CYP2C9 and CYP2C19 in vitro. When used simultaneously with warfarin, an increase in prothrombin time was observed. When used simultaneously with coumarin derivatives, short-term monitoring of prothrombin time is necessary at the beginning and end of imatinib therapy, as well as when changing the imatinib dosage regimen. As an alternative, warfarin should be used concomitantly with low molecular weight heparins with caution. With the simultaneous use of imatinib with chemotherapeutic drugs in high doses, transient liver toxicity may develop in the form of increased activity of liver transaminases and hyperbilirubinemia. Monitoring of liver function should be considered when imatinib is combined with chemotherapy regimens that have the potential to cause liver dysfunction. In vitro, imatinib inhibits the cytochrome 1450 isoenzyme CYP2C6 at the same concentrations at which it inhibits the CYP3A4 isoenzyme. With simultaneous use of imatinib at a dose of 400 mg 2 times a day with metoprolol, a substrate of the CYP2C6 isoenzyme. There is a moderate decrease in the metabolism of metoprolol, accompanied by an increase in Cmax and AUC by approximately 21%. Given the moderate increase in the effects of metoprolol, a change in the dosage regimen is not required when used simultaneously with imatinib. In vitro, imatinib inhibits the O-glucuronidation of paracetamol, and therefore caution should be exercised when imatinib is used concomitantly with paracetamol (especially when using high doses of paracetamol). In patients who have undergone thyroidectomy and are receiving hormone replacement therapy with levothyroxine sodium, a decrease in its plasma concentration may occur when used simultaneously with imatinib. The issue of drug interactions between imatinib and chemotherapy drugs in patients with Ph+ OJIJI has not been sufficiently studied. Caution must be exercised when using imatinib and chemotherapy drugs simultaneously due to a possible increase in the risk of developing drug complications, such as hepatotoxicity, myelosuppression, etc. There are reports of the development of liver damage with the simultaneous use of imatinib and asparaginase.