Imatinib pills 400mg, 30pcs

Composition

Active ingredients: imatinib mesylate – 514,25 mg in terms of imatinib is 400 mg;

excipients: lactose anhydrous – 80,174 mg, croscarmellose sodium – 10.00 mg, povidone K-30 – 12,545 mg, talc – 7,527 mg, magnesium stearate – 10,00 mg crospovidone -15,50 mg.

the composition of the shell: film coating Insta-Coat – of 19.5 mg (polyethylene glycol – 3.9 mg, hypromellose – 7,8 mg, talc – 3.9 mg, titanium dioxide (E 171) and 3.9 mg), iron oxide red (E 172) – 0,50 mg.

Pharmacological properties

Pharmacotherapeutic group: Antitumor agent, inhibitor of protein tyrosine kinase APX:

L. 01. X. E. 01 Imatinib

Pharmacodynamics :

Imatinib has a selective inhibitory effect on the Wash-Abl – tyrosine kinase enzyme, formed by the fusion of the Bcr (breakpoint cluster region) gene region and the Abl (Abelson) proto-oncogene, at the cellular level, selectively suppresses proliferation and causes apoptosis of cell lines expressing Bcr-Abl-tyrosine kinase, including immature leukemia cells formed in patients with Philadelphia cell line-positive cells. chromosome of chronic myeloid leukemia and acute lymphoblastic leukemia.

Imatinib selectively inhibits Bcr-Abl-positive colonies derived from the blood cells of patients with chronic myeloid leukemia.

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

Activation of platelet growth factor receptors or the tyrosine kinase Abl fragment can cause the development of both myelodysplastic/myeloproliferative diseases, as well as hypereosinophilic syndrome and chronic eosinophilic leukemia and bulging dermatofibrosarcoma.

Activation of the c-Kit tyrosine kinase receptor and platelet growth factor receptors may underlie the pathogenesis of systemic mastocytosis. Imatinib inhibits cell signaling and cell proliferation resulting from dysregulation of platelet and stem cell growth factors, the c-Kit receptor, and the Abl tyrosine kinase fragment.

Pharmacokinetics:

Absorption rate

After oral use, the bioavailability of the drug is on average 98%. The coefficient of variation for the area under the concentration-time curve (AUC) indicator is 40-60%.

When taking the drug with a high-fat diet, in comparison with 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 blood plasma by about 11%, AUC – by about 7.4%) and a slowdown in the absorption rate (an increase in the time to reach the maximum concentration of imatinib in blood plasma by 1.5 hours). Distribution

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

Metabolism

Imatinib is mainly metabolized in the liver to form the main metabolite (N-demethylated piperazine derivative) that circulates in the bloodstream. In vitro, the imatinib metabolite has a pharmacological activity similar to that of the parent substance. The metabolite’s AUC value is about 16% of that of imatinib. Binding of the metabolite to plasma proteins is similar to that of imatinib.

Deduction

After taking one dose, the drug is eliminated from the body within 7 days, mainly in the form of metabolites (68% – by the intestines and 13% – by the kidneys). Approximately 25% of the dose is excreted unchanged (20% by the intestines and 5% by the kidneys). The elimination half-life of imatinib is approximately 18 hours.

With repeated doses of the drug 1 time a day, the pharmacokinetic parameters do not change, and the equilibrium concentration of imatinib exceeds the initial one by about 1.5-2.5 times.

Pharmacokinetics in special patient groups

In patients over 65 years of age, the volume of distribution increases by approximately 12%, which is clinically insignificant. For patients with a body weight of 50 kg, the average clearance of imatinib is approximately 8.5 l/h, and for patients with a body weight of 100 kg – about 11.8 l/h.

However, these differences are not significant and do not require adjustment of the dosage of the drug depending on the patient’s body weight. The pharmacokinetics of imatinib are gender-independent. Changes in the clearance and volume of distribution of imatinib when used concomitantly with other drugs are insignificant and do not require a dose change.

In children and adolescents under 18 years of age, as in adults, imatinib is rapidly absorbed after oral use. 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 AUC0-24 values in children and adolescents on the 1st and 8th days after repeated use of the drug at a dose of 340 mg/m2 1 time per day, an increase in the value of this indicator by 1.7 times is noted, indicating the accumulation of imatinib.

Based on a combined population pharmacokinetic analysis in children with hematological diseases, it was shown that imatinib clearance is directly proportional to body surface area, while other demographic parameters (age, body weight, and body mass index) do not have a clinically significant effect on imatinib exposure.

In patients with varying degrees of hepatic impairment, the mean AUC values do not increase.

When imatinib is used in patients with mild or moderate renal impairment (creatinine clearance > 30 ml/min), there is an increase in plasma exposure of approximately 1.5-2.0 times, corresponding to an increase in the concentration of acidic alpha-glycoproteins (the main plasma proteins binding to imatinib).

No correlation was found between the drug exposure and the severity of renal impairment.

Indications

– were First detected positive for the Philadelphia chromosome (Ph+)

chronic myeloid leukemia (CML) in children and adults;

– Ph+ CML in chronic phase at the failure of previous therapy with interferon Alfa or in the phase of acceleration or blast crisis in children and adults;

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

– recurrent or refractory Ph+ ALL in adults as monotherapy;

– myelodysplastic/myeloproliferative diseases associated with genetic rearrangements of the receptor for the growth factor platelet adult patients;

systemic mastocytosis in adults 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-PDGFR alpha tyrosinekinase;

an inoperable and/or metastatic malignant gastrointestinal stromal tumors positive for c-Kit (CD 117) in adult patients;

– adjuvant therapy gastrointestinalny stromal tumors, positive for c-Kit (CD 117) in adult patients;

an inoperable, recurrent and/or metastatic wybuchowa dermatofibrosarcoma in adult patients.

Use during pregnancy and lactation

Pregnancy

Currently, there are no data on the use of imatinib in pregnant women. Animal studies have shown toxic effects on reproductive function, but the potential risk to the fetus is not yet known. Imatinib is contraindicated during pregnancy. Women of childbearing age should use reliable methods of contraception during imatinib therapy and for at least 3 months thereafter.

Breast-feeding

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

Contraindications

-Hypersensitivity to the Active ingredient or any other component of the drug.

– Pregnancy, breast-feeding period.

– Children under 2 years of age (efficacy and safety are currently unknown).

With caution: Imatinib should be used with caution in patients with severe hepatic insufficiency, severe renal impairment (creatinine clearance less than 30 ml/min), cardiovascular diseases or risk factors for heart failure, as well as during regular hemodialysis procedures. Caution should be exercised when imatinib is co-administered with drugs that inhibit the CYP3A4 isoenzyme, strong inducers of the CYP3A4 isoenzyme, with drugs that are substrates of the CYP3A4 isoenzyme, paracetamol, warfarin (see the section “Interaction with other drugs”).

Side effects

At the advanced stage of malignant diseases, the assessment of adverse events (AES) of the drug is difficult due to symptoms associated with multiple concomitant disorders, their progression, and the use of various medications.

Imatinib is generally well-tolerated with prolonged daily oral use in adults and children with CML. Most AES were mild to moderate in severity. Side effects were similar in almost all patients treated with imatinib for various indications.

However, myelosuppression was less common in patients with malignant gastrointestinal stromal tumors; intracancer bleeding was observed only in this group of patients.The most common AES associated with taking the drug were neutropenia, thrombocytopenia, anemia, headache, dyspepsia, edema, weight gain, nausea, vomiting, diarrhea, myalgia, muscle cramps, rash, weakness, abdominal pain. All these phenomena were easily stopped.

Peripheral edema was frequently observed, mainly in the periorbital region and lower extremities.

Other serious AES associated with imatinib include hepatotoxicity, acute renal failure, hypophosphatemia, respiratory disorders, tumor lysis syndrome, and growth retardation in children.

Concomitant side effects such as pleural effusion, ascites, pulmonary edema, and rapid weight gain with or without peripheral edema can be classified as “fluid retention” and in some cases can be severe (including life-threatening).

In clinical studies in patients with CML and with inoperable and/or metastatic malignant gastrointestinal stromal tumors, the following adverse events were noted, listed below by organ and system, indicating the frequency of their occurrence: very often (>1/10), often (>>1/100 >>< 1/10), infrequently (> 1/1000 < 1/10), infrequently (><1/100), rarely (>1/10000 – <1/100), rarely (><1/1000), very rarely (:

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

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

Disorders of the blood and lymphatic system: very often-neutropenia, thrombocytopenia, anemia; often-pancytopenia, febrile neutropenia, infrequently-thrombocytemia, lymphopenia, bone marrow hematopoiesis suppression, eosinophilia, lymphadenopathy; rarely-hemolytic anemia.

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

Mental disorders: often – insomnia; infrequently-depression, anxiety, decreased libido; rarely-confusion.

Nervous system disorders: very often-headache; often-dizziness, paresthesia, taste disorders, hypesthesia; infrequently-migraine, drowsiness, fainting, peripheral neuropathy, memory disorders, sciatica, restless legs syndrome, tremor, hemorrhagic stroke, brain edema; rarely – increased intracranial pressure, convulsions, optic neuritis.

Visual disturbances: often-edema of the eyelids, increased lacrimation, conjunctival hemorrhage, conjunctivitis, dry eye syndrome, blurred vision; infrequently-eye irritation, eye pain, orbital edema, hemorrhage in the sclera of the eye, retinal hemorrhage, blepharitis, macular edema, rarely – cataracts, edema of the optic disc, glaucoma, vitreous hemorrhage.

Hearing disorders and labyrinth disorders: infrequently – vertigo, tinnitus, hearing loss.

Disorders of the cardiovascular system: infrequently – palpitations, chronic heart failure, pulmonary edema, tachycardia, hot flashes, hemorrhages, thrombosis/embolism; rarely – arrhythmias, atrial fibrillation, sudden cardiac arrest; myocardial infarction, angina, pericardial effusion, increased and decreased blood pressure, hematomas, subdural hematomas, cold extremities, Raynaud’s syndrome, pericarditis; cardiac tamponade; very rare rarely – anaphylactic shock.

Respiratory, thoracic and mediastinal disorders: often-nosebleeds, shortness of breath, cough; infrequently – pleural effusion, pain in the pharynx or larynx, pharyngitis, acute respiratory failure, interstitial pneumonia; rarely – pleural pain, pulmonary fibrosis, pulmonary hypertension, pulmonary hemorrhages.

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

Liver and biliary tract disorders: often-increased activity of “liver” enzymes, infrequently-jaundice, hepatitis, hyperbilirubinemia, rarely-liver failure, liver necrosis.

Skin and subcutaneous tissue disorders: very often – periorbital edema, dermatitis, eczema, skin rash; often – facial edema, pruritus, erythema, dry skin, alopecia, night sweats, photosensitization reactions; infrequently – pustular rash, bruises, increased sweating, urticaria, ecchymosis, increased predisposition to hematoma formation, hypotrichosis, hyperpigmentation/hypopigmentation of the skin, exfoliative dermatitis, nail damage, folliculitis, petechiae, psoriasis, purpura, bullous rash; rarely – acute febrile neutrophilic dermatosis (Sweet’s syndrome), nail discoloration, angioedema, erythema multiforme, leukoclastic vasculitis, Stevens-Johnson syndrome, acute generalized pustular exanthema, palmar – plantar erythrodysesthesia, lichenoid keratosis, lichen planus toxic epidermal necrolysis; frequency unknown – drug-induced rash with eosinophilia and systemic symptoms.

Musculoskeletal and connective tissue disorders: very common-muscle spasms and cramps, musculoskeletal pain, including myalgia, arthralgia, bone pain; often-joint swelling; infrequently-muscle and joint stiffness, rarely-muscle weakness, arthritis; frequency unknown – growth retardation in children, avascular necrosis / necrosis of the femoral head, rhabdomyolysis/myopathy.

Disorders of the kidneys and urinary system: infrequently – kidney pain, hematuria, acute renal failure, frequent urination.

Disorders of the endocrine system, genitals and mammary glands: infrequently-gynecomastia, erectile dysfunction, menorrhagia, menstrual disorders, sexual dysfunction, nipple pain, breast enlargement, scrotal edema; very rarely-bleeding from a corpus luteum cyst/ovary.

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

Description of individual NSAs

Hematopoietic depression

The frequency of hematopoietic depression and its severity were maximal when the drug was used in high doses and, apparently, depended on the stage of CML. Overall, hematopoietic suppression during imatinib use in CML patients was reversible and in most cases did not require discontinuation of the drug or reduction of its dose. Withdrawal of the drug was required in a small number of cases. Phenomena such as pancytopenia, lymphopenia and hematopoietic depression were also noted.

Hemorrhage/bleeding

The most frequent clinically significant bleeding events were those from the gastrointestinal tract (GI). Most often, they occurred in patients with advanced stages of XMJ1 and in patients with malignant gastrointestinal stromal tumors, in which they may be a consequence of the underlying disease (bleeding from the tumor due to tumor necrosis).

In patients with XMJI, whose hematopoiesis was already suppressed before the start of treatment, hemorrhages in the central nervous system or gastrointestinal tract are often also noted during treatment. It has been established that patients with acute leukemia often experience bleeding/hemorrhage due to thrombocytopenia or thrombocytopathy.

Edema and fluid retention

Edema is a common 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, periorbital edema occurs, with a slightly lower frequency – edema 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 CML, the incidence of heart failure was higher than in patients of other categories, which can be explained by their weakened condition in general. The same trend was observed for renal failure in patients with edema and fluid retention. The majority of patients with edema and fluid retention were elderly (older than 65 years).

Rash and severe skin adverse reactions

A number of patients treated with imatinib had generalized erythematous, maculopapular, and pruritic rashes that could resolve on their own despite continued treatment with the drug. Some patients experienced pruritus without rash; in some cases, erythroderma was present.

Rash occurred in approximately one-third of all patients treated with imatinib for all indications. Often, the rash is accompanied by itching and usually manifests as erythematous, spotty-papular lesions on the forearm, trunk, or face.

Although in most cases the rash is mild and resolves without treatment, in more severe cases, temporary or complete discontinuation of the drug may be necessary. As a rule, the severity of the rash decreases after the appointment of antihistamines and topical corticosteroids. In some cases, it is necessary to use glucocorticosteroids for systemic use.

Hepatotoxicity

The drug may have a toxic effect on the liver. Violations of the biochemical parameters of liver function, as a rule, consist in a slight increase in the activity of aminotransferases and an increase in the concentration of bilirubin in the blood serum.

Toxic effects on the liver usually occur during the first two months of treatment, but in some cases they also occur 6-12 months after the start of treatment. As a rule, after discontinuation of the drug, the biochemical parameters of liver function normalize within 1-4 weeks. There have been cases of cytolytic and cholestatic hepatitis and liver failure, in some cases accompanied by a fatal outcome.

Obstruction, perforation, or ulcer of the stomach or intestines

In a small proportion of patients treated with imatinib, ulceration of the gastrointestinal tract was noted, which in some cases may be due to the local irritant 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 malignant gastrointestinal stromal tumors, tumor necrosis may occur against the background of a tumor response, which in rare cases leads to perforation. Obstruction of the gastrointestinal tract most often occurred in patients with malignant stromal tumors of the gastrointestinal tract, in which it can be caused by metastases or adhesions that have occurred as a result of previous surgery on the gastrointestinal tract (in the case of using the drug as an adjuvant therapy).

Severe AES from the respiratory system

Severe (sometimes fatal) cases AES have been reported with imatinib, including acute respiratory failure, pulmonary hypertension, interstitial lung disease, and pulmonary fibrosis. Concomitant diseases of the cardiovascular or respiratory system may exacerbate the severity of AES.

If any of the side effects listed in the instructions get worse, or the patient notices any other side effects that are not listed in the instructions, you should inform your doctor.

Interaction

When imatinib is co-administered with drugs that inhibit the cytochrome P450 CYP3A4 isoenzyme (ketoconazole, itraconazole, erythromycin, clarithromycin, protease inhibitors (indinavir, lopinavir, ritonavir, saquinavir, telaprevir, nelfinavir, boceprevir), posaconazole, voriconazole, telithromycin), it is possible to slow down the metabolism imatinib and an increase in its concentration in blood plasma. Caution should be exercised when imatinib is co-administered with drugs that inhibit the CYP3A4 isoenzyme.

On the contrary, 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, phenobarbital, phosphenytoin, primidone) can lead to an acceleration of imatinib metabolism and, as a result, to a decrease in its concentration in blood plasma and ineffectiveness of therapy. Concomitant use of imatinib and strong inducers of the CYP3A4 isoenzyme should be avoided.

When imatinib and simvastatin are co-administered, there is a 2-and 3.5-fold increase in the Cmax and AUC of simvastatin, respectively, which is a consequence of inhibition of CYP3A4 by imatinib.

Caution is recommended when using imatinib concomitantly with drugs that are substrates of the CYP3A4 isoenzyme and have a narrow range of therapeutic concentrations (for example, cyclosporine, pimozide, tacrolimus, sirolimus, ergotamine, fentanyl, terfenadine, bortezomib, docetaxel, quinidine). Imatinib may increase serum concentrations of other drugs that are metabolized by the CYP3A4 isoenzyme (triazolo-benzodiazepines, dihydropyridine, slow calcium channel blockers, most HMG-CoA reductase inhibitors, including statins).

Imatinib also inhibits the CYP2C9 isoenzyme and the CYP2C19 isoenzyme in vitro. Prolongation of prothrombin time was observed when imatinib was co-administered with warfarin. When used concomitantly with coumarin derivatives, short-term monitoring of prothrombin time is necessary at the beginning and end of therapy with the drug, as well as when changing the dosage regimen of imatinib. As an alternative to warfarin, the use of low-molecular-weight heparins should be considered.

When imatinib is combined with high-dose chemotherapeutic agents, transient hepatic toxicity may develop in the form of an increase in the level of “hepatic” transaminases and hyperbilirubinemia.

In patients undergoing thyroidectomy and receiving hormone replacement therapy with levothyroxine sodium, it is possible to reduce its plasma concentration when combined with imatinib.

The issue of drug interaction between imatinib and chemotherapy drugs in patients with Ph+ OJIJI has not been sufficiently studied. Caution should be exercised when imatinib is co-administered with chemotherapeutic agents due to the possible increased risk of drug complications, such as hepatotoxicity, myelosuppression, etc.

Liver damage has been reported with the combined use of imatinib and asparaginase.

Monitoring of liver function should be considered when combining imatinib and chemotherapy regimens that may potentially cause liver function disorders. In vitro, imatinib inhibits the cytochrome P 450 CYP2D6 isoenzyme at the same concentrations as it inhibits the CYP3A4 isoenzyme.

When imatinib is used together with metoprolol, a substrate of the CYP2D6 isoenzyme, there is a moderate decrease in metoprolol metabolism, accompanied by an increase in Cmax and AUC. Given the moderate increase in the effects of drugs that are substrates of the CYP2D6 isoenzyme (for example, metoprolol), when they are co-administered with imatinib, there is no need to change the dosage regimen. In vitro, imatinib inhibits O-glucuronidation of paracetamol/acetaminophen.

Caution should be exercised when using imatinib together with paracetamol/acetaminophen due to the possible development of acute liver failure with a fatal outcome in patients.

How to take, course of use and dosage

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

Patients who are unable to swallow the tablet whole, such as children, can take the drug in a diluted form; tablets are diluted with water or apple juice. The required number of tablets or is placed in a glass, filled with liquid (approximately 100 ml of 400 mg tablet liquid) and stirred with a spoon; as a result, a suspension is formed.

The resulting suspension should be taken orally immediately after preparation.

In chronic myeloid leukemia (CML), the recommended dose of Imatinib depends on the phase of the disease. In the chronic phase of CML, the dose is 400 mg / day; in the acceleration phase and in the blast crisis-600 mg/day. The drug should be taken once a day.

Treatment with the drug is carried out as long as the clinical effect persists. In the absence of significant side effects and neutropenia or thrombocytopenia not associated with leukemia, it is possible to increase the dose from 400 mg to 600 mg or up to 800 mg in patients in the chronic phase of the disease, and from 600 mg to 800 mg per day in patients in the acceleration phase and in blast crisis.

Such an increase in the dose may be necessary if CML progresses (at any stage), if there is no satisfactory hematological response after 3 months of treatment, a cytogenetic response after 12 months of therapy, or if the previously achieved hematological and/or cytogenetic response is lost.

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

In Ph+acute lymphoblastic leukemia, the recommended dose of Imatinib is 600 mg per day.

For myelodysplastic/myeloproliferative diseases, the recommended dose of Imatinib is 400 mg per day.

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

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

When using the drug as 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 has not been established.

For inoperable, recurrent and/or metastatic bulging dermatofibrosarcoma, the recommended dose of Imatinib is 800 mg per day. In case of systemic mastocytosis in the absence of D816V c-Kit mutation, the recommended dose of Imatinib is 400 mg per day. In cases of unknown mutation status and insufficient effectiveness of previous therapy, the recommended dose is 400 mg per day.

In systemic mastocytosis caused by abnormal FIP1L1-PDGFR a-tyrosine kinase resulting from the fusion of Fip likel and PDGFR genes, the recommended initial dose is 100 mg per day. If there is insufficient effectiveness and no pronounced side effects, the dose may be increased to 400 mg / day.

In adult patients with hypereosinophilic syndrome and/or chronic eosinophilic leukemia (HES/HEL), the recommended dose is 400 mg/day. In patients with HES/HEL caused by abnormal FIP1L1-PDGFR a-tyrosine kinase, the recommended initial dose is 100 mg per day. If there is insufficient effectiveness and no pronounced side effects, the dose may be increased to 400 mg / day.

Patients with impaired liver function

Since imatinib is primarily metabolized in the liver, imatinib should be administered at a minimum daily dose of 400 mg in patients with mild, moderate, or severe hepatic impairment. If undesirable toxic effects develop, the dose of the drug should be reduced. Caution should be exercised when prescribing the drug to patients with severe hepatic insufficiency.

Patients with impaired renal function

The kidneys do not play a significant role in the elimination of imatinib and its metabolites. In patients with impaired renal function or in patients who require systematic hemodialysis, treatment with imatinib should be initiated with the minimum effective dose of 400 mg once a day, with caution. If imatinib is intolerant, the initial dose of the drug can be reduced, and if it is not effective enough, it can be increased.

Elderly patients

Elderly patients do not need to adjust the dosage regimen of the drug.

Correction of the dosage regimen with the development of non-hematological side effects of the drug

If any serious non-hematological side effect associated with taking the drug develops, therapy should be interrupted until the situation is resolved. Treatment can then be resumed at a dose that depends on the severity of the observed side effect.

If the bilirubin concentration and liver transaminase activity in the blood serum are 3 and 5 times higher than the upper limit of normal (ULN), respectively, treatment with the drug should be temporarily suspended until the bilirubin concentration decreases to less than 1.5 CVI and the activity of “liver” transaminases to less than 2.5 CVI.

Imatinib therapy 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 dosage regimen with the development of serious side effects from the hematopoietic system (severe thrombocytopenia, neutropenia)

If neutropenia and thrombocytopenia occur, temporary discontinuation of the drug or a reduction in its dose is required, depending on the severity of these adverse events. In patients with systemic mastocytosis (SM) and hypereosinophilic syndrome and / or chronic eosinophilic leukemia (HES/HEL) caused by abnormal FIP1L1-PDGFR a-tyrosine kinase (initial dose of imatinib 100 mg), in the case of a decrease in the absolute number of neutrophils <1.0 * 109/l and / or the number of platelets:

1. discontinue imatinib until the absolute neutrophil and platelet counts are ≥1.5 * 109/L and ≥75* 109 / L, respectively.

2. resume treatment with imatinib at the dose used prior to discontinuation of therapy.

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

1. discontinue imatinib until the absolute neutrophil and platelet counts are ≥1.5 * 109/L and ≥75* 109 / L, respectively.

2. resume treatment with imatinib at the dose used prior to discontinuation of therapy.

In case of repeated decrease in the number of neutrophils <1.0* 109/l and / or the number of platelets 

In the acceleration phase and blast crisis of CML in children and adults and in Ph+ acute lymphoblastic leukemia in adult patients (the initial dose for adults is 600 mg, for children – 340 mg/m2) in the case of a decrease in the absolute number of neutrophils <0.5 * 109/l and / or the number of platelets:

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

2. if cytopeia is not associated with leukemia, reduce the dose of imatinib 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, discontinue imatinib until the absolute number of neutrophils and platelets is >1 * 109/l and >>20* 109/L, respectively; then resume treatment with imatinib at a dose of 300 mg (in children-260 mg / m2).

In case of inoperable, recurrent and / or metastatic bulging dermatofibrosarcoma (initial dose of imatinib 800 mg) with a decrease in the absolute neutrophil count <1.0*109/l and / or platelet count:

1. discontinue imatinib until the absolute neutrophil and platelet counts are ≥1.5 * 109/L and ≥75*109 / L, respectively.

2. resume treatment with imatinib 600 mg.

If the neutrophil count decreases again <1.0*109/l and/or the platelet count <50* 109/L, repeat the steps indicated in paragraph 1, and then resume treatment with imatinib at a reduced dose of 400 mg.

Overdose

Individual cases of imatinib overdose have been reported. In one case, when taking imatinib at a dose of 1200-1600 mg for 1-10 days, patients were observed:: nausea, vomiting, diarrhea, rash, erythema, swelling, facial swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite.

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

When using the drug at a dose of 6400 mg once (information from a published source), the patient developed nausea, vomiting, abdominal pain, hyperthermia, facial edema, a decrease in the number of neutrophils and an increase in the activity of “hepatic” transaminases. When taking the drug at a dose of 8-10 mg once, vomiting and gastrointestinal pain were noted.

When taking the drug at a dose of 400 mg once in children aged 3 years, vomiting, anorexia, diarrhea were noted, and at a dose of 980 mg – a decrease in the number of white blood cells and diarrhea. Treatment: Medical supervision and symptomatic therapy are recommended. The antidote is unknown.

Special instructions

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

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

Experience with imatinib in children with CML under 2 years of age is limited, and experience with imatinib for other indications is limited in patients under 18 years of age. Careful growth monitoring is recommended for children using imatinib, as there are reports of stunted growth.

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

Patients with heart and kidney diseases should be closely monitored.

Due to the fact that when using imatinib in 1-2% of cases, there is a pronounced fluid retention, it is recommended to regularly monitor the body weight of patients. In case of rapid unexpected weight gain, the patient should be examined and, if necessary, temporarily stop imatinib therapy and / or prescribe diuretics.

The highest incidence of fluid retention is observed in elderly patients with concomitant cardiovascular diseases. In some cases, severe fluid retention can have a severe course with a fatal outcome.

When using the drug, patients with liver diseases should regularly conduct a clinical blood test and determine the” activity ” of liver enzymes. Since there are reports of the development of hypothyroidism with Imatinib in patients undergoing thyroidectomy and receiving levothyroxine sodium replacement therapy, it is necessary to regularly determine the concentration of thyroid-stimulating hormone in this category of patients.

In patients with hypereosinophilia syndrome and heart disease, there are isolated cases of cardiogenic shock/left ventricular failure at the beginning of Imatinib therapy. These adverse events are stopped after the introduction of systemic glucocorticosteroids, taking measures aimed at maintaining blood circulation, and temporarily withdrawing Imatinib.

In patients with MDS/MPD and high levels of eosinophils, an ECG study should be performed and the serum concentration of cardiospecific troponin should be determined. If deviations from the norm are detected at the beginning of therapy, the possibility of prophylactic use of systemic glucocorticosteroids (1-2 mg/kg) for 1-2 weeks simultaneously with imatinib should be considered.

Bleeding was observed both in the abdominal organs and in the liver, depending on the location of the tumor foci.

Reliable methods of contraception should be used during imatinib therapy and for at least 3 months thereafter.

It is possible to increase the activity of” hepatic ” transaminases or bilirubin in patients with XMJI, which is controlled by reducing the dose of the drug or temporarily interrupting treatment.

Due to the risk of developing tumor lysis syndrome, clinically expressed dehydration and elevated uric acid levels in patients should be corrected if necessary before using imatinib.

Influence on the ability to drive vehicles and mechanisms:Some side effects of the drug, such as dizziness and blurred vision, can negatively affect the ability to drive a car and perform potentially dangerous activities that require increased concentration and speed of psychomotor reactions. If the above-mentioned adverse events occur, you should refrain from performing these types of activities.

Storage conditions

In a dark place at a temperature not exceeding 25 °C. The drug should be kept out of the reach of children.

Shelf

life is 2 years.

Active ingredient

Imatinib

Conditions of release from pharmacies

By prescription

Dosage form

Tablets