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

active substance: imatinib mesylate - 128.56 mg in terms of imatinib - 100 mg; Excipients: lactose anhydrous - 350.94 mg, croscarmellose sodium - 10.00 mg, povidone K-30 - 7.50 mg, talc - 3.00 mg, magnesium stearate - 5.00 mg, crospovidone - 15.00 mg.

shell composition: film coating Insta-Coat 6.0 mg (polyethylene glycol 1.2 mg, hypromellose 2.4 mg, talc 1.2 mg, titanium dioxide (E 171) 1.2 mg), iron oxide red ( E 172) -4.00 mg.

Dosage of 400 mg

active substance: imatinib mesylate - 514.25 mg in terms of imatinib - 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.

shell composition: film coating Insta-Coat - 19.5 mg (polyethylene glycol - 3.9 mg, hypromellose - 7.8 mg, talc - 3.9 mg, titanium dioxide (E 171) - 3.9 mg), iron oxide red ( E 172) 0.50 mg.

Description:

Dosage of 100 mg: Round biconvex tablets covered with a film coat of a brownish-pink color. On the cross section, the core of the tablet is light yellow in color.

Dosage of 400 mg: Oblong biconvex tablets covered with a film coat of a brownish-pink color. On the cross section, the core of the tablet is light yellow in color.

Pharmacotherapeutic group:An antitumour agent, a protein tyrosine kinase inhibitor

ATX: & nbsp

L.01.X.E.01 Imatinib

Pharmacodynamics:

Imatinib has a selective inhibitory effect on the B-Abl-tyrosine kinase enzyme formed by the fusion of the Bcr (breakpoint cluster region) and the Abl (Abelson) protooncogene at the cellular level, selectively inhibits proliferation and induces apoptosis of the Bcr-Abl tyrosine kinase expressing cell lines , including immature leukemia cells formed in patients with positive for the Philadelphia chromosome chronic myeloid leukemia and acute lymphoblastic leukemia.

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

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

Activation of receptors to platelet growth factors or Abl-tyrosine kinase fragment can cause the development of both myelodysplastic / myeloproliferative diseases,and hypereosinophilic syndrome and chronic eosinophilic leukemia and swelling dermatofibrosarcoma. Activation of the c-Kit receptor tyrosine kinase and receptors for platelet growth factors may underlie the pathogenesis of systemic mastocytosis. Imatinib inhibits cell signaling and cell proliferation resulting from impaired regulation of platelet and stem cell growth factors, c-Kit receptor, and tyrosine kinase Abl.

Pharmacokinetics:

Absorption

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

When taking the drug with a high-fat diet, compared with fasting, there is a slight decrease in the degree of absorption (a decrease in the maximum concentration of imatinib in the blood plasma by about 11%, AUC - about 7.4%) and slowing the rate of absorption achieving the maximum concentration of imatinib in the blood plasma for 1.5 h). Distribution

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

Metabolism

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

Excretion

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

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

Pharmacokinetics in specific patient groups

In patients older than 65 years, the volume of distribution increases by about 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 correction of the dosage of the drug depending on the patient's body weight. The pharmacokinetics of imatinib does not depend on sex. Changes in clearance and volume distribution of imatinib with simultaneous use with other drugs are insignificant and do not require dose changes.

In children and adolescents under the age of 18, as in adults, imatinib quickly absorbed after ingestion. AUC in this group of patients in a dose range of 260 and 340 mg / m²is similar to that in adults in the dose range of 400 mg and 600 mg, respectively. When comparing the values of AUC in children and adolescents₀_-₂₄on the 1 st and 8 th days after repeated administration of the drug at a dose of 340 mg / m²Once a day, the increase in the value of this indicator is observed 1.7 times, indicating the cumulation of imatinib. 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.

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

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

Indications:

- The newly identified positive for the Philadelphia chromosome (Ph +)

chronic myeloid leukemia (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 blast crisis in children and adults;

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

- recurrent or refractory Ph + OLD 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 unknown c-Kit mutation status;

- hypereosinophilic 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 the active substance or any other component of the drug.

- Pregnancy, the period of breastfeeding.

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

Carefully:It should be used with caution Imatinib in patients with severe hepatic insufficiency, severe impairment of renal function (creatinine clearance less than 30 ml / min), cardiovascular disease or in the presence of risk factors for heart failure, and regular hemodialysis procedure.Caution should be exercised when using imatinib with CYP3A4 isozyme inhibitory drugs, CYP3A4 isozymes, with preparations that are substrates of the CYP3A4 isoenzyme, paracetamol, and warfarin (see "Interactions with Other Drugs").

Pregnancy and lactation:

Pregnancy

Currently, there are no data on the use of imatinib in pregnant women. Studies on animals 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 during therapy with imatinib and at least 3 months after should use reliable methods of contraception.

Lactation

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

Dosing and Administration:

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

Patients who are not able to swallow the whole tablet, for example children, the drug can be taken in a diluted form; pills diluted with water or apple juice. The required amount of tablets or placed in a glass, pour liquid (approximately 100 ml of tablet liquid 400 mg) and stir with a spoon; as a result, a slurry is formed. The resulting suspension should be taken immediately after preparation.

In chronic myelogenous leukemia (XML), 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 phase of acceleration and with a blast crisis - 600 mg / day. The drug should be taken 1 time per day. Treatment with the drug is carried out as long as the clinical effect remains. In the absence of severe side effects and neutropenia or thrombocytopenia not associated with leukemia, a dose increase from 400 mg to 600 mg or up to 800 mg in patients in the chronic phase of the disease and from 600 mg to 800 mg per day in patients in the accelerated phase and with a blast cry. Such a dose increase may be necessary in the progression of XML (at any stage), in the absence of a satisfactory hematologic response after 3 months of treatment,cytogenetic response after 12 months of therapy or loss of previously achieved hematologic and / or cytogenetic response.

Calculation of the dosing regimen in children over 2 years of age is based on body surface area. Doses of 340 mg / m²per day are recommended in children with chronic phase XML and accelerating phase. The total daily dose in children should not exceed 600 mg. The daily dose of the drug can be taken simultaneously or divided into 2 equal doses - in the morning and in the evening.

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

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

With 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 an inadequate response, an increase in the daily dose of Imatinib from 400 mg to 600 mg or up to 800 mg is possible.

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

When the drug is used as an 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.

With inoperable, relapsing and / or metastatic swelling dermatofibrosarcoma, the recommended dose of Imatinib is 800 mg per day. In systemic mastocytosis in the absence of D816V c-Kit mutation, the recommended dose of Imatinib is 400 mg per day. With an unknown mutational status and insufficient effectiveness of previous therapy, the recommended dose is 400 mg per day.

In systemic mastocytosis caused by an abnormal FIP1L1-PDGFR atrorosine kinase, resulting from the fusion of the Fip likel and PDGFR genes, the recommended initial dose is 100 mg per day. With insufficient effectiveness and no significant side effects, an increase in the dose to 400 mg / day is possible.

With a hypereosinophilic syndrome and / or chronic eosinophilic leukemia (HES / HAL) in adults, the recommended dose is 400 mg / day. In patients with HES / HAL caused by abnormal FIP1L1-PDGFR a-tyrosine kinase, the recommended initial dose is 100 mg per day. With insufficient effectiveness and no significant side effects, an increase in the dose to 400 mg / day is possible.

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 of the drug should be reduced. Caution is advised to prescribe the drug to patients with severe hepatic impairment.

Patients with impaired renal function

Kidneys do not play a significant role in the excretion of imatinib and its metabolites. In patients with impaired renal function or in patients requiring systematic hemodialysis, treatment with imatinib should begin with a minimum effective dose of 400 mg once daily, being careful. With imatinib intolerance, the initial dose of the drug can be reduced, with insufficient effectiveness - increased.

Elderly patients

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

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

With the development of any serious non-hematologic side effect associated with taking the drug, therapy should be discontinued until the situation resolves.The treatment can then be resumed at a dose that depends on the severity of the observed side effect. With increasing bilirubin concentration and transaminase activity in the blood serum 3 and 5 times higher than the upper limit of the norm (VGN), respectively, treatment with the drug should be temporarily suspended until the concentration of bilirubin is reduced to less than 1.5xVGN and the activity of "hepatic" transaminases to less than 2,5хVGN.

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

In the event of neutropenia and thrombocytopenia, a temporary withdrawal of the drug or a decrease in its dose is required, depending on the severity of these undesirable phenomena. In systemic mastocytosis (CM) and hypereosinophilic syndrome and / or chronic eosinophilic leukemia (HES / HAL) 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 <50 *10⁹/ l is recommended:

1. abolish imatinib until the absolute number of neutrophils and platelets is ≥1.5 *10⁹/ l and ≥75 * 10⁹/ l, respectively;

2. resume treatment with imatinib at a dose used before the interruption of therapy.

In the chronic phase of XML in children and adults, malignant gastrointestinal stromal tumors, myelodysplastic / myeloproliferative diseases, SM and HES / CHAL in adult patients (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 <50 * 10⁹/ l is recommended:

1. abolish imatinib until the absolute number of neutrophils and platelets is ≥1.5 * 10⁹/ l and ≥75 * 10⁹/ l, respectively;

2. resume treatment with imatinib at a dose used before the interruption of therapy.

In the case of a repeated decrease in the number of neutrophils <1.0 * 10⁹/ l and / or the number of platelets <50 *10⁹/ l should repeat the actions indicated in paragraph 1, and then resume treatment with imatinib in a reduced dose of 300 mg (in children - 260 mg / m²). In the phase of acceleration 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 <1.0 *10⁹/ l after one or more months of treatment is recommended:

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

2. if the 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, cancel 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).

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

1. abolish imatinib until the absolute number of neutrophils and platelets is ≥1.5 *10⁹/ l and ≥75 *10⁹/ l, respectively;

2. to resume treatment with imatinib at a dose of 600 mg.

In the case of a repeated decrease in the number of neutrophils <1.0 *10⁹/ l and / or the number of platelets <50 * 10⁹/ l, repeat the actions described in paragraph 1, and then resume treatment with imatinib at a reduced dose of 400 mg.

Side effects:

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

With prolonged daily intake of adults and children with CML Imatinib in general, is well tolerated. Most AEs were mild or moderate. Side effects were similar in almost all patients who received imatinib for various indications. However, in patients with malignant gastrointestinal stromal tumors, myelosuppression was less common; Intra-tumoral bleeding was observed only in this group of patients. The most frequent AEs associated with taking the drug were neutropenia, thrombocytopenia, anemia, headache, dyspepsia, swelling, weight gain, nausea, vomiting, diarrhea, myalgia, muscle cramps, rash, weakness, abdominal pain. All these phenomena were easily stopped.

Often there were peripheral edema, mainly in the periorbital region and lower limbs.

Other serious AEs with imatinib are hepatotoxicity, acute renal failure, hypophosphatemia, respiratory system disorders, tumor lysis syndrome and growth retardation in children.

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

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

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

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

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

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

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

Impaired nervous system: very often - headache; often - dizziness, paresthesia, taste disorder, hypoesthesia; infrequently - migraine, drowsiness, fainting, peripheral neuropathy, memory impairment, sciatica, restless leg syndrome, tremor, hemorrhagic stroke, cerebral edema; 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, bleeding in the sclera of the eye, retinal hemorrhage, blepharitis, macular edema, rarely - cataract, edema of the optic nerve, glaucoma, vitreous hemorrhage.

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

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

Disturbances from the respiratory system, chest and mediastinal organs: often - nosebleeds, dyspnea, cough; infrequently - a pleural effusion,pain in the pharynx or larynx, pharyngitis, acute respiratory failure, interstitial pneumonia; rarely - pleural pain, pulmonary fibrosis, pulmonary hypertension, pulmonary hemorrhage.

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

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

Disturbances from the skin and subcutaneous tissues: very often - periorbital edema, dermatitis, eczema, skin rash; often puffiness of the face,itching, erythema, dry skin, alopecia, night sweats, photosensitivity reactions; infrequently - pustular rash, bruises, increased sweating, urticaria, ecchymosis, increased predisposition to education hematomas, hypotrichosis, hyperpigmentation / hypopigmentation of the skin, exfoliative dermatitis, nail damage, folliculitis, petechiae, psoriasis, purpura, bullous rash; rarely acute febrile neutrophilic dermatosis (Sweet syndrome), nail color change, angioedema, erythema multiforme, leukoclastic vasculitis, Stevens-Johnson syndrome, acute generalized pustular exanthema, palmar-plantar erythrodysesthesia, lichenoid keratosis, red flat lichen; toxic epidermal necrolysis; frequency unknown - drug rash with eosinophilia and systemic symptoms.

Disturbances from the osteomuscular and connective tissue: very often - muscle spasms and cramps, musculoskeletal pain, including myalgia, arthralgia, bone pain; often swelling of the joints; infrequent - stiffness of muscles and joints, rarely - muscle weakness, arthritis; frequency is unknown - growth retardation in children,avascular necrosis / necrosis of the head of the femur, rhabdomyolysis / myopathy.

Impaired kidney and urinary system: infrequently - kidney pain, hematuria, acute renal failure, frequent urination.

Disorders from the endocrine system, genital organs and mammary glands: infrequently - gynecomastia, erectile dysfunction, menorrhagia, menstrual irregularities, sexual dysfunction, pain in the nipples, enlargement of the mammary glands, swelling of the scrotum; very rarely - bleeding from the cyst of the yellow body / ovary.

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

Description of individual AEs

Inhibition of hematopoiesis

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

Hemorrhage / bleeding

The most frequent clinically significant bleeding were bleeding from the gastrointestinal tract (GI tract). Most often they appeared in patients with late stages of XMJ1 and in patients with malignant stromal tumors of the gastrointestinal tract, in which they can be a consequence of the underlying disease (bleeding from the tumor due to tumor necrosis). In patients with XMJI, whose hematopoiesis was suppressed already before the start of treatment, during treatment often hemorrhages in the central nervous system or gastrointestinal tract are also noted. It was found that patients with leukemia with acute development of the disease often have bleeding / hemorrhage caused by thrombocytopenia or thrombocytopathy.

Swelling and fluid retention

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

Rash and severe skin undesirable reactions

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

Hepatotoxicity

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

A small proportion of patients who received imatinib, ulceration of the gastrointestinal tract was noted, which in some cases may be a consequence of the local irritating effect of imatinib. Hemorrhagic necrosis of the tumor, as well as obstruction and perforation of the gastrointestinal tract, were most often observed in patients with malignant stromal tumors of the gastrointestinal tract. In the case of metastatic malignant stromal tumors of the gastrointestinal tract, necrosis of the tumor can occur against a background of a tumor response, which in rare cases leads to perforation. Gastrointestinal obstruction occur most often in patients with malignant gastrointestinal stromal tumors in which its cause may be metastasized or adhesions resulting from prior operations on the gastrointestinal tract (in the case of using the drug as adjuvant therapy).

Heavy AEs from the respiratory system

Severe (sometimes accompanied by fatal) AEs were noted against the background of imatinib,namely acute respiratory failure, pulmonary hypertension, interstitial lung disease and pulmonary fibrosis. The concomitant pathology of the cardiovascular or respiratory systems can aggravate the severity of AEs.

If any of the side effects listed in the manual are aggravated, or the patient has noticed any other side effects not listed in the instructions, you should notify the doctor.

Overdose:

There are reports of individual cases of imatinib overdose. In one case, imatinib in a dose of 1200-1600 mg for 1-10 days in patients were observed: nausea, vomiting, diarrhea, rash, erythema, swelling, swelling of the face, increased fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain , headache, decreased appetite.

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

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

While taking the drug at a dose of 400 mg single dose in children aged 3 years were observed vomiting, anorexia, diarrhea, and at a dose of 980mg - reducing the number of leukocytes and diarrhea. Treatment: medical supervision and symptomatic therapy are recommended. The antidote is unknown.

Interaction:

With the simultaneous use of imatinib with drugs that inhibit the cytochrome P450 isoenzyme CYP3A4 (ketoconazole, itraconazole, erythromycin, clarithromycin, protease inhibitors (indinavir, lopinavir, ritonavir, saquinavir, telaprevir, nelfinavir, boceprevir), posaconazole, voriconazole, Telithromycin) may slow the metabolism of imatinib and an increase in its concentration in blood plasma. Caution is needed when combined with imatinib with inhibitor preparations of the CYP3A4 isoenzyme.

On the contrary, the simultaneous use of drugs which are inducers isoenzyme CYP3A4 (e.g., rifampicin, dexamethasone preparations from Hypericum perforatum, antiepileptic drugs: carbamazepine, oxcarbazepine, phenytoin, phenobarbital, fosphenytoin, primidone) may accelerate imatinib metabolism and as a consequence, to a decrease in its plasma concentration and treatment failure.Simultaneous use of imatinib and strong inducers of the CYP3A4 isoenzyme should be avoided.

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

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

Imatinib also inhibits the isoenzyme CYP2C9 and the isoenzyme CYP2C19 in vitro. Elongation of prothrombin time was observed with the combined use of imatinib with warfarin. With simultaneous application with coumarin derivatives, short-term prothrombin time monitoring at the beginning and end of therapy with the drug, as well as a change in the dosage regimen of imatinib, is necessary.As an alternative to warfarin, consideration should be given to the use of low molecular weight heparins.

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

In patients undergoing thyroidectomy and receiving HRT levothyroxine sodium may decrease its plasma concentrations when used with imatinib.

The question of the drug interaction of imatinib and preparations for chemotherapy in patients with Ph + OJIJI is insufficiently studied. Caution should be exercised in the joint use of imatinib and chemotherapeutic drugs in connection with the possible increase in the risk of developing drug complications, such as hepatotoxicity, myelosuppression, etc.

There are reports of the development of liver damage in the joint use of imatinib and asparaginase.

With a combination of imatinib and regimens of chemotherapy that can potentially cause liver dysfunction, liver function should be monitored. In vitro imatinib inhibits the cytochrome P450 isoenzyme CYP2D6 at the same concentrations in which it inhibits the CYP3A4 isoenzyme.

When imatinib is used together with metoprolol, the 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 isoenzyme CYP2D6 (eg, metoprolol), when combined 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 along with paracetamol / acetaminophen because of the possible development in patients with acute hepatic insufficiency with a fatal outcome.

Special instructions:

Treatment with imatinib should be done only 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 treatment of children with CML younger than 2 years is limited, the experience of using the drug for other indications is limited in patients younger than 18 years.It is recommended to carry out a careful growth control in children using imatinib, in connection with the available reports of a delay in their growth.

When imatinib is used, regular clinical blood testing and monitoring of liver function (transaminase, bilirubin, alkaline phosphatase) are recommended.

Care should be taken to monitor patients with heart and kidney disease.

Due to the fact that when imatinib is applied in 1-2% of cases, there is a marked fluid retention, it is recommended to regularly monitor the body weight of patients. In the case of a rapid, sudden increase in body weight, a patient should be examined and, if necessary, temporarily discontinued therapy with imatinib and / or diuretics. The highest frequency of fluid retention is observed in elderly patients with concomitant cardiovascular diseases. In some cases, severe fluid retention may have a severe course with a fatal outcome.

When the drug is used, patients with liver disease should regularly perform a clinical blood test and determine the "activity" of liver enzymes.Since there are reports of the development of hypothyroidism against the background of the use of Imatinib in patients who have undergone thyroidectomy and are receiving substitution therapy with levothyroxine sodium, it is necessary to regularly determine the concentration of thyroid-stimulating hormone in this category of patients.

In patients with hypereosinophilia syndrome and heart disease, at the beginning of Imatinib therapy, individual cases of cardiogenic shock / left ventricular failure are noted. These undesirable phenomena stop after the introduction of systemic glucocorticosteroids, the adoption of measures aimed at maintaining blood circulation, and the temporary cancellation of Imatinib.

In patients with MDS / MPD and high levels of eosinophils, ECG testing should be performed and the serum concentration of cardiospecific troponin should be determined. When detecting abnormality of the start of therapy should be considered a prophylactic use of systemic glucocorticoids (1-2 mg / kg) for 1-2 weeks, concurrently with imatinib.

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

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

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

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

Effect on the ability to drive transp. cf. and fur:Some side effects of the drug, such as dizziness and blurred vision, can adversely affect the ability to drive and perform potentially dangerous activities requiring increased concentration and speed of psychomotor reactions. If the above undesirable phenomena occur, you should refrain from performing these activities.

Form release / dosage:Tablets 100 mg, 400 mg.

Packaging:

Primary packaging of medicinal product:

For 10 tablets per blister of Al / PVC.For 1, 2, 3 or 5 blisters together with instructions for use are put in a cardboard box.

Secondary packaging of medicinal product:

10, 20, 24, 30, 36, 48, 50, 60, 96, 100, 120 or 180 tablets in a polymer can of high-density polyethylene with a pull-on lid with first opening control. Free space is filled with cotton wool. On the bank stick a label from paper label or writing or from polymer materials, self-adhesive. Banks, together with an equal number of instructions for use, are placed in a group package - a box of corrugated cardboard (for hospitals).

JSC Pharmsynthez, Russia:

Secondary packaging of medicinal product:

For 1, 2, 3 or 5 blisters together with instructions for use are put in a cardboard box.

Storage conditions:In the dark place at a temperature of no higher than 25 ° C. The drug should be stored out of the reach of children.

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

Terms of leave from pharmacies:On prescription

Registration number:LP-002816

Date of registration:13.01.2015 / 29.08.2016

Expiration Date:13.01.2020

The owner of the registration certificate:ArSiAi Synthesis, ZAOArSiAi Synthesis, ZAO

Manufacturer: & nbsp

Biosynthesis Laboratories Private Limited India

Information update date: & nbsp14.11.2017

Illustrated instructions

Instructions

Imatinib (Imatinib)